rs72492997

Variant names:

• chr3-10046582-G-T
• rs72492997
• NM_001018115.3:c.1137G>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001018115.3(FANCD2):​c.1137G>T​(p.Val379Val) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (0 hom., cov: 44)
  • Exomes 𝑓: 0.19 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 splice_region, synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.08
• Publications: 19 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 3-10046582-G-T is Benign according to our data. Variant chr3-10046582-G-T is described in ClinVar as Benign. ClinVar VariationId is 342260.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.08 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.1137G>T	p.Val379Val	splice_region synonymous	Exon 15 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1137G>T	p.Val379Val	splice_region synonymous	Exon 15 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1137G>T	p.Val379Val	splice_region synonymous	Exon 15 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.1137G>T	p.Val379Val	splice_region synonymous	Exon 15 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1137G>T	p.Val379Val	splice_region synonymous	Exon 15 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1137G>T	p.Val379Val	splice_region synonymous	Exon 15 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.445 AC: 55909 AN: 125696 Hom.: 0 Cov.: 44

Gnomad AFR AF: 0.466

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.385

Gnomad SAS AF: 0.383

Gnomad FIN AF: 0.445

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.435

GnomAD2 exomes AF: 0.138 AC: 20677 AN: 150050 AF XY: 0.135

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.0445

Gnomad ASJ exome AF: 0.0744

Gnomad EAS exome AF: 0.0694

Gnomad FIN exome AF: 0.297

Gnomad NFE exome AF: 0.185

Gnomad OTH exome AF: 0.0898

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.185 AC: 138739 AN: 749832 Hom.: 0 Cov.: 42 AF XY: 0.191 AC XY: 71545 AN XY: 375272

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

African (AFR) AF: 0.248 AC: 4075 AN: 16428

American (AMR) AF: 0.154 AC: 3974 AN: 25828

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 3745 AN: 14362

East Asian (EAS) AF: 0.234 AC: 5794 AN: 24776

South Asian (SAS) AF: 0.0784 AC: 3562 AN: 45410

European-Finnish (FIN) AF: 0.396 AC: 13932 AN: 35172

Middle Eastern (MID) AF: 0.306 AC: 1061 AN: 3472

European-Non Finnish (NFE) AF: 0.172 AC: 95163 AN: 551734

Other (OTH) AF: 0.228 AC: 7433 AN: 32650

⚠️ 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 Data not reliable, filtered out with message: InbreedingCoeff AF: 0.445 AC: 55942 AN: 125774 Hom.: 0 Cov.: 44 AF XY: 0.442 AC XY: 27101 AN XY: 61290

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

African (AFR) AF: 0.466 AC: 16539 AN: 35476

American (AMR) AF: 0.396 AC: 4786 AN: 12100

Ashkenazi Jewish (ASJ) AF: 0.442 AC: 1263 AN: 2856

East Asian (EAS) AF: 0.385 AC: 1574 AN: 4090

South Asian (SAS) AF: 0.382 AC: 1437 AN: 3758

European-Finnish (FIN) AF: 0.445 AC: 3783 AN: 8498

Middle Eastern (MID) AF: 0.453 AC: 107 AN: 236

European-Non Finnish (NFE) AF: 0.451 AC: 25397 AN: 56324

Other (OTH) AF: 0.435 AC: 738 AN: 1696

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.334 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Fanconi anemia complementation group D2 (2)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group A (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	9.7
DANN	Benign	0.77
PhyloP100		1.1
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs72492997; hg19: chr3-10088266; COSMIC: COSV55036171; COSMIC: COSV55036171;