rs56041034

Variant names:

• chr3-10073260-A-C
• rs56041034
• NM_001018115.3:c.2613A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-10073260-A-C
• chr3-10073260-A-G
• chr3-10073260-A-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001018115.3(FANCD2):​c.2613A>C​(p.Lys871Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000145 in 1,586,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000069 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: -0.0360
• Publications: 12 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010343969).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.2613A>C	p.Lys871Asn	missense	Exon 28 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.2613A>C	p.Lys871Asn	missense	Exon 28 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.2613A>C	p.Lys871Asn	missense	Exon 28 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.2613A>C	p.Lys871Asn	missense	Exon 28 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.2613A>C	p.Lys871Asn	missense	Exon 28 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.2613A>C	p.Lys871Asn	missense	Exon 28 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.000826 AC: 124 AN: 150074 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00204

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000731

Gnomad ASJ AF: 0.000581

Gnomad EAS AF: 0.000992

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000954

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000312

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.000204 AC: 51 AN: 249662 AF XY: 0.0000886

Gnomad AFR exome AF: 0.00187

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000689 AC: 99 AN: 1436662 Hom.: 0 Cov.: 30 AF XY: 0.0000559 AC XY: 40 AN XY: 716006

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00173 AC: 57 AN: 32976

American (AMR) AF: 0.000157 AC: 7 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85648

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.000350 AC: 2 AN: 5716

European-Non Finnish (NFE) AF: 0.0000257 AC: 28 AN: 1089362

Other (OTH) AF: 0.0000673 AC: 4 AN: 59420

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000872 AC: 131 AN: 150188 Hom.: 0 Cov.: 32 AF XY: 0.000942 AC XY: 69 AN XY: 73252

African (AFR) AF: 0.00220 AC: 90 AN: 40852

American (AMR) AF: 0.000731 AC: 11 AN: 15054

Ashkenazi Jewish (ASJ) AF: 0.000581 AC: 2 AN: 3442

East Asian (EAS) AF: 0.000995 AC: 5 AN: 5026

South Asian (SAS) AF: 0.00 AC: 0 AN: 4734

European-Finnish (FIN) AF: 0.0000954 AC: 1 AN: 10484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000312 AC: 21 AN: 67318

Other (OTH) AF: 0.000481 AC: 1 AN: 2078

Alfa AF: 0.000307 Hom.: 0

ExAC AF: 0.00219 AC: 266

EpiCase AF: 0.0000546

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Fanconi anemia (2)
-	1	1	Fanconi anemia complementation group D2 (2)
-	-	1	FANCD2-related disorder (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.087	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.84
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.036
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.17
Sift	Benign	0.13	T
Sift4G	Uncertain	0.0070	D
Polyphen		0.15	B
Vest4		0.16
MutPred		0.33		Loss of methylation at K871 (P = 9e-04)
MVP		0.59
MPC		0.23
ClinPred		0.028	T
GERP RS		-2.4
Varity_R		0.18
gMVP		0.37
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs56041034; hg19: chr3-10114944; COSMIC: COSV55033983; COSMIC: COSV55033983;