rs35625434

chr3-10043144-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):c.983G>A(p.Arg328Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00148 in 1,613,774 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. R328R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (21 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: -0.106

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0026809573).
• BP6: Variant 3-10043144-G-A is Benign according to our data. Variant chr3-10043144-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00173 (264/152244) while in subpopulation SAS AF= 0.0106 (51/4820). AF 95% confidence interval is 0.00847. There are 4 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.983G>A	p.Arg328Gln	missense_variant	12/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.983G>A	p.Arg328Gln	missense_variant	12/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 263 AN: 152126 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00956

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00884

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00446 AC: 1120 AN: 251246 Hom.: 11 AF XY: 0.00415 AC XY: 563 AN XY: 135798

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.0202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00783

Gnomad SAS exome AF: 0.00797

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00145 AC: 2126 AN: 1461530 Hom.: 21 Cov.: 32 AF XY: 0.00157 AC XY: 1141 AN XY: 727086

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0198

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0101

Gnomad4 SAS exome AF: 0.00806

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000270

Gnomad4 OTH exome AF: 0.00179

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74432

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.00974

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.0106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00110 Hom.: 2

Bravo AF: 0.00250

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00392 AC: 476

Asia WGS AF: 0.00577 AC: 20 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The FANCD2 p.Arg328Gln variant was identified in 1 of 48 proband chromosomes (frequency: 0.021) from individuals with Fanconi anemia (Nie_2019). The p.R328Q variant was identified as a heterozygous variant in a patient with multiple primary malignant neoplasms who also carried multiple variants in other cancer genes, including BRCA2 and MLH3 (Wang_2019_PMID:30942098). The variant was identified in dbSNP (ID: rs35625434) and ClinVar (classified as benign by Invitae and likely benign by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics) but was not identified in Cosmic. The variant was identified in control databases in 1133 of 268136 chromosomes (11 homozygous) at a frequency of 0.004225 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1, non-cancer). The variant was observed in the following populations: Latino in 711 of 35082 chromosomes (freq: 0.02027), South Asian in 243 of 30516 chromosomes (freq: 0.007963), East Asian in 147 of 19252 chromosomes (freq: 0.007636), Other in 22 of 6696 chromosomes (freq: 0.003286), African in 5 of 23600 chromosomes (freq: 0.000212) and European (non-Finnish) in 5 of 118032 chromosomes (freq: 0.000042), but was not observed in the Ashkenazi Jewish, or European (Finnish) populations. The p.Arg328 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 three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2020	- -

Fanconi anemia complementation group D2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 05, 2022	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	May 06, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Oct 03, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	2.7
Dann	Benign	0.88
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.72	T;T;.
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.040	N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.011
Sift	Benign	0.52	T;T;T
Sift4G	Benign	0.92	T;T;T
Polyphen		0.0030	.;B;B
Vest4		0.11
MVP		0.22
MPC		0.17
ClinPred		0.00056	T
GERP RS		-5.5
Varity_R		0.015
gMVP		0.099

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

Publications

LitVar

Other links and lift over

dbSNP: rs35625434; hg19: chr3-10084828;