3-10065966-A-C

Variant names:

• chr3-10065966-A-C
• rs758718558
• NM_001018115.3:c.2372A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001018115.3(FANCD2):​c.2372A>C​(p.Asn791Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N791S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.05
• Publications: 3 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.906

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.2372A>C	p.Asn791Thr	missense	Exon 25 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.2372A>C	p.Asn791Thr	missense	Exon 25 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.2372A>C	p.Asn791Thr	missense	Exon 25 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.2372A>C	p.Asn791Thr	missense	Exon 25 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.2372A>C	p.Asn791Thr	missense	Exon 25 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.2372A>C	p.Asn791Thr	missense	Exon 25 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451940 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 722972

African (AFR) AF: 0.00 AC: 0 AN: 33272

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86016

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1103044

Other (OTH) AF: 0.00 AC: 0 AN: 60062

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.075	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MutPred		0.50		Loss of stability (P = 0.1887)
MVP		0.91
MPC		0.64
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.91
gMVP		0.73
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs758718558; hg19: chr3-10107650;