ENST00000431693.1:c.711G>C

Variant names:

• chr3-10039861-G-C
• rs17032283
• ENST00000431693.1:c.711G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000431693.1(FANCD2):​c.711G>C​(p.Leu237Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 1,613,274 control chromosomes in the GnomAD database, including 24,498 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3457 hom., cov: 31)
  • Exomes 𝑓: 0.17 (21041 hom.)
• Consequence: FANCD2 ENST00000431693.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.127
• Publications: 17 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 3-10039861-G-C is Benign according to our data. Variant chr3-10039861-G-C is described in ClinVar as Benign. ClinVar VariationId is 257086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.127 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000431693.1. 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.695+16G>C		intron	N/A	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.695+16G>C		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.695+16G>C		intron	N/A	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000431693.1	TSL:1	c.711G>C	p.Leu237Leu	synonymous	Exon 8 of 8	ENSP00000399354.1	Q9BXW9-4
	FANCD2	ENST00000675286.1	MANE Select	c.695+16G>C		intron	N/A	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.695+16G>C		intron	N/A	ENSP00000287647.3	Q9BXW9-1

Frequencies

GnomAD3 genomes AF: 0.197 AC: 29900 AN: 151736 Hom.: 3453 Cov.: 31

Gnomad AFR AF: 0.320

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.150

Gnomad EAS AF: 0.0656

Gnomad SAS AF: 0.160

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.171

GnomAD2 exomes AF: 0.161 AC: 40539 AN: 251290 AF XY: 0.160

Gnomad AFR exome AF: 0.333

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0657

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.166 AC: 242005 AN: 1461422 Hom.: 21041 Cov.: 33 AF XY: 0.165 AC XY: 120195 AN XY: 727006

African (AFR) AF: 0.331 AC: 11085 AN: 33468

American (AMR) AF: 0.158 AC: 7066 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4096 AN: 26136

East Asian (EAS) AF: 0.0568 AC: 2255 AN: 39698

South Asian (SAS) AF: 0.180 AC: 15488 AN: 86212

European-Finnish (FIN) AF: 0.123 AC: 6580 AN: 53402

Middle Eastern (MID) AF: 0.166 AC: 941 AN: 5680

European-Non Finnish (NFE) AF: 0.166 AC: 184456 AN: 1111732

Other (OTH) AF: 0.166 AC: 10038 AN: 60374

GnomAD4 genome AF: 0.197 AC: 29925 AN: 151852 Hom.: 3457 Cov.: 31 AF XY: 0.192 AC XY: 14232 AN XY: 74220

African (AFR) AF: 0.320 AC: 13225 AN: 41366

American (AMR) AF: 0.145 AC: 2203 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.150 AC: 521 AN: 3464

East Asian (EAS) AF: 0.0656 AC: 339 AN: 5170

South Asian (SAS) AF: 0.161 AC: 774 AN: 4812

European-Finnish (FIN) AF: 0.116 AC: 1224 AN: 10546

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10994 AN: 67950

Other (OTH) AF: 0.171 AC: 361 AN: 2106

Alfa AF: 0.177 Hom.: 494

Bravo AF: 0.207

Asia WGS AF: 0.116 AC: 405 AN: 3478

EpiCase AF: 0.163

EpiControl AF: 0.159

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Fanconi anemia complementation group D2 (3)
-	-	2	not provided (2)
-	-	1	Fanconi anemia (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.8
DANN	Benign	0.41
PhyloP100		-0.13
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs17032283; hg19: chr3-10081545; COSMIC: COSV55047412;