rs145522204

chr3-10052475-A-G

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.1634A>G(p.Asn545Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 1,611,800 control chromosomes in the GnomAD database, including 50 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0072 (47 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 2.82

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=0.0064072013).
• BP6: Variant 3-10052475-A-G is Benign according to our data. Variant chr3-10052475-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 134312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10052475-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00444 (676/152250) while in subpopulation NFE AF= 0.0074 (503/68008). AF 95% confidence interval is 0.00686. There are 3 homozygotes in gnomad4. There are 314 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.1634A>G	p.Asn545Ser	missense_variant	18/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.1634A>G	p.Asn545Ser	missense_variant	18/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 676 AN: 152132 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.00157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00740

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00421 AC: 1059 AN: 251344 Hom.: 1 AF XY: 0.00410 AC XY: 557 AN XY: 135878

Gnomad AFR exome AF: 0.000987

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00708

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00718 AC: 10477 AN: 1459550 Hom.: 47 Cov.: 30 AF XY: 0.00684 AC XY: 4965 AN XY: 726118

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00230

Gnomad4 ASJ exome AF: 0.000459

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000476

Gnomad4 FIN exome AF: 0.00550

Gnomad4 NFE exome AF: 0.00857

Gnomad4 OTH exome AF: 0.00770

GnomAD4 genome AF: 0.00444 AC: 676 AN: 152250 Hom.: 3 Cov.: 30 AF XY: 0.00422 AC XY: 314 AN XY: 74452

Gnomad4 AFR AF: 0.00156

Gnomad4 AMR AF: 0.00347

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00740

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00648 Hom.: 1

Bravo AF: 0.00433

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00814 AC: 70

ExAC AF: 0.00406 AC: 493

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Nov 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 11, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Aug 27, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 06, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	FANCD2: BP4, BS2 -

Fanconi anemia complementation group A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	11
Dann	Benign	0.27
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.86
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.85	D;D;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0064	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.72	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.75	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.060	.;B;B
Vest4		0.090
MVP		0.37
MPC		0.12
ClinPred		0.0019	T
GERP RS		1.3
Varity_R		0.029
gMVP		0.19

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: rs145522204; hg19: chr3-10094159; COSMIC: COSV99811739; COSMIC: COSV99811739;