rs73126218

Positions:

• chr3-10046659-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001018115.3(FANCD2):​c.1214A>G​(p.Asn405Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (0 hom., cov: 49)
  • Exomes 𝑓: 0.39 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.211

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024337769).
• BP6: Variant 3-10046659-A-G is Benign according to our data. Variant chr3-10046659-A-G is described in ClinVar as [Benign]. Clinvar id is 342263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10046659-A-G is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.1214A>G	p.Asn405Ser	missense_variant	15/44	ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.1214A>G	p.Asn405Ser	missense_variant	15/44		NM_001018115.3	ENSP00000502379.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 65086 AN: 141890 Hom.: 0 Cov.: 49 FAILED QC

Gnomad AFR AF: 0.478

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.420

Gnomad ASJ AF: 0.457

Gnomad EAS AF: 0.411

Gnomad SAS AF: 0.411

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.460

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.452

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.389 AC: 373029 AN: 959700 Hom.: 0 Cov.: 62 AF XY: 0.387 AC XY: 184921 AN XY: 478068

Gnomad4 AFR exome AF: 0.430

Gnomad4 AMR exome AF: 0.279

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.254

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.399

Gnomad4 OTH exome AF: 0.397

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.459 AC: 65132 AN: 141990 Hom.: 0 Cov.: 49 AF XY: 0.457 AC XY: 31673 AN XY: 69286

Gnomad4 AFR AF: 0.478

Gnomad4 AMR AF: 0.420

Gnomad4 ASJ AF: 0.457

Gnomad4 EAS AF: 0.411

Gnomad4 SAS AF: 0.410

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.453

Alfa AF: 0.368 Hom.: 0

ExAC AF: 0.412 AC: 50070

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia complementation group D2 Benign:1

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:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2017

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	10
DANN	Benign	0.88
DEOGEN2	Benign	0.078	.;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.85	T;T;.
MetaRNN	Benign	0.0024	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.98	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.81	T;T;T
Polyphen		0.022	.;B;B
Vest4		0.042
MPC		0.12
ClinPred		0.00058	T
GERP RS		0.31
Varity_R		0.032
gMVP		0.081

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs73126218; hg19: chr3-10088343; COSMIC: COSV55032016; COSMIC: COSV55032016;