chr3-10039303-A-G

Variant names:

• chr3-10039303-A-G
• rs35173688
• NM_001018115.3:c.516A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.516A>G​(p.Ile172Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,613,798 control chromosomes in the GnomAD database, including 172 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (95 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (77 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 0.263
• 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]

FANCD2 Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group D2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016033947).
• BP6: Variant 3-10039303-A-G is Benign according to our data. Variant chr3-10039303-A-G is described in ClinVar as Benign. ClinVar VariationId is 134327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0622 is higher than 0.05.

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.516A>G	p.Ile172Met	missense	Exon 8 of 44	NP_001018125.1
	FANCD2	NM_033084.6		c.516A>G	p.Ile172Met	missense	Exon 8 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.516A>G	p.Ile172Met	missense	Exon 8 of 42	NP_001361183.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.516A>G	p.Ile172Met	missense	Exon 8 of 44	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.516A>G	p.Ile172Met	missense	Exon 8 of 43	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.516A>G	p.Ile172Met	missense	Exon 8 of 44	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.0185 AC: 2821 AN: 152136 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00779

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.00462 AC: 1162 AN: 251288 AF XY: 0.00333

Gnomad AFR exome AF: 0.0643

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00176 AC: 2570 AN: 1461544 Hom.: 77 Cov.: 30 AF XY: 0.00154 AC XY: 1121 AN XY: 727094

African (AFR) AF: 0.0619 AC: 2072 AN: 33458

American (AMR) AF: 0.00318 AC: 142 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.0000890 AC: 99 AN: 1111788

Other (OTH) AF: 0.00399 AC: 241 AN: 60390

GnomAD4 genome AF: 0.0186 AC: 2827 AN: 152254 Hom.: 95 Cov.: 32 AF XY: 0.0180 AC XY: 1343 AN XY: 74454

African (AFR) AF: 0.0642 AC: 2666 AN: 41528

American (AMR) AF: 0.00778 AC: 119 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.0157 AC: 33 AN: 2108

Alfa AF: 0.00449 Hom.: 52

Bravo AF: 0.0216

ESP6500AA AF: 0.0704 AC: 310

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00581 AC: 705

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0000546

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:3

Sep 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 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.

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Apr 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Fanconi anemia Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:1

Mar 25, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BA1, BP4_Moderate c.516A>G located in exon 8 of the FANCD2 gene, is predicted to result in the substitution of isoleucine by methionine at codon 172, p.(Ile172Met). The variant allele was found in 1507/23612 alleles (52 homozygotes), with a filter allele frequency of 6% at 99% confidence, within the African population in the gnomAD v2.1.1 database (non-cancer data set)(BA1). The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score for this variant (0.025) suggests that it does not affect the protein function according to Pejaver 2022 thresholds (PMID: 36413997)(BP4_Moderate). This variant has been identified in the ClinVar database (8x benign, 1x likely benign) and in the LOVD database (1x benign, 1x likely benign). Based on currently available information, the variant c.516A>G is classified as a benign variant according ACMG guidelines.

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

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	0.068
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.75
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.84
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.63	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.1	N
PhyloP100		0.26
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.025
Sift	Benign	1.0	T
Sift4G	Benign	0.69	T
Polyphen		0.0070	B
Vest4		0.20
MVP		0.46
MPC		0.15
ClinPred		0.0019	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.047
gMVP		0.26
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs35173688; hg19: chr3-10080987; COSMIC: COSV104599186;