NM_001018115.3:c.3446C>T

Variant names:

• chr3-10087244-C-T
• rs147675860
• NM_001018115.3:c.3446C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):​c.3446C>T​(p.Ala1149Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,605,114 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1149G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00069 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00034 (6 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.17
• Publications: 6 publications found

Genes affected

FANCD2 (HGNC:3585): (FA complementation group D2) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group D2. This protein is monoubiquinated in response to DNA damage, resulting in its localization to nuclear foci with other proteins (BRCA1 AND BRCA2) involved in homology-directed DNA repair. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048253834).
• BP6: Variant 3-10087244-C-T is Benign according to our data. Variant chr3-10087244-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000691 (102/147574) while in subpopulation EAS AF = 0.0128 (65/5064). AF 95% confidence interval is 0.0103. There are 2 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001018115.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.3446C>T	p.Ala1149Val	missense	Exon 34 of 44	NP_001018125.1
	FANCD2	NM_033084.6		c.3446C>T	p.Ala1149Val	missense	Exon 34 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.3446C>T	p.Ala1149Val	missense	Exon 34 of 42	NP_001361183.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.3446C>T	p.Ala1149Val	missense	Exon 34 of 44	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.3446C>T	p.Ala1149Val	missense	Exon 34 of 43	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.3446C>T	p.Ala1149Val	missense	Exon 34 of 44	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.000691 AC: 102 AN: 147552 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.000884

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0128

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000496

GnomAD2 exomes AF: 0.00125 AC: 314 AN: 251104 AF XY: 0.00101

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0158

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000339 AC: 494 AN: 1457540 Hom.: 6 Cov.: 34 AF XY: 0.000268 AC XY: 194 AN XY: 725172

African (AFR) AF: 0.000512 AC: 17 AN: 33230

American (AMR) AF: 0.0000448 AC: 2 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25996

East Asian (EAS) AF: 0.00989 AC: 391 AN: 39546

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52700

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5746

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1109344

Other (OTH) AF: 0.000947 AC: 57 AN: 60162

GnomAD4 genome AF: 0.000691 AC: 102 AN: 147574 Hom.: 2 Cov.: 31 AF XY: 0.000739 AC XY: 53 AN XY: 71718

African (AFR) AF: 0.000883 AC: 35 AN: 39660

American (AMR) AF: 0.00 AC: 0 AN: 14748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.0128 AC: 65 AN: 5064

South Asian (SAS) AF: 0.00 AC: 0 AN: 4626

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9432

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67374

Other (OTH) AF: 0.000493 AC: 1 AN: 2030

Alfa AF: 0.000775 Hom.: 3

Bravo AF: 0.000831

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00121 AC: 147

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCD2: BP4, BS1, BS2

Aug 02, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The FANCD2 p.Ala1149Val variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs147675860), ClinVar (classified as a VUS by Illumina for Fanconi Anemia, likely benign by Center for Pediatric Genomic Medicine at Children's Mercy Hospital and Clinics and benign by Invitae for Fanconi Anemia) and Cosmic (FATHMM prediction: neutral; score=0.19). The variant was identified in control databases in 352 of 281318 chromosomes (5 homozygous) at a frequency of 0.001251 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 320 of 19928 chromosomes (freq: 0.01606), African in 22 of 24706 chromosomes (freq: 0.000891), Other in 2 of 7158 chromosomes (freq: 0.000279), Latino in 2 of 35354 chromosomes (freq: 0.000057), European (non-Finnish) in 5 of 128722 chromosomes (freq: 0.000039) and South Asian in 1 of 30612 chromosomes (freq: 0.000033), but was not observed in the Ashkenazi Jewish or European (Finnish) populations. The p.Ala1149 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

Fanconi anemia complementation group D2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Fanconi anemia Benign:1

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	13
DANN	Benign	0.74
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		1.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.88	N
REVEL	Benign	0.025
Sift	Benign	0.43	T
Sift4G	Benign	0.32	T
Polyphen		0.20	B
Vest4		0.090
MVP		0.55
MPC		0.18
ClinPred		0.0028	T
GERP RS		2.8
Varity_R		0.019
gMVP		0.086
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs147675860; hg19: chr3-10128928; COSMIC: COSV55033772;