NM_001018115.3:c.864C>T

Variant names:

• chr3-10042639-C-T
• rs780547790
• NM_001018115.3:c.864C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001018115.3(FANCD2):​c.864C>T​(p.Ser288Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000063 (0 hom.)
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -2.00
• Publications: 1 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-10042639-C-T is Benign according to our data. Variant chr3-10042639-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 526456.
• BP7: Synonymous conserved (PhyloP=-2 with no splicing effect.

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.864C>T	p.Ser288Ser	synonymous	Exon 11 of 44	NP_001018125.1
	FANCD2	NM_033084.6		c.864C>T	p.Ser288Ser	synonymous	Exon 11 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.864C>T	p.Ser288Ser	synonymous	Exon 11 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.864C>T	p.Ser288Ser	synonymous	Exon 11 of 44	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.864C>T	p.Ser288Ser	synonymous	Exon 11 of 43	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.864C>T	p.Ser288Ser	synonymous	Exon 11 of 44	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152058 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000151 AC: 38 AN: 251402 AF XY: 0.000125

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000630 AC: 92 AN: 1461462 Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 727066

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.000807 AC: 32 AN: 39670

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000477 AC: 53 AN: 1111688

Other (OTH) AF: 0.0000994 AC: 6 AN: 60378

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152058 Hom.: 0 Cov.: 32 AF XY: 0.0000943 AC XY: 7 AN XY: 74258

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000860 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	FANCD2-related disorder (1)
-	-	1	Fanconi anemia (1)
-	1	-	Fanconi anemia complementation group D2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	2.0
DANN	Benign	0.75
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs780547790; hg19: chr3-10084323; COSMIC: COSV55047821; COSMIC: COSV55047821;