NM_001018115.3:c.4098T>G

Variant names:

• chr3-10096385-T-G
• rs2272125
• NM_001018115.3:c.4098T>G

Variant summary

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

The NM_001018115.3(FANCD2):​c.4098T>G​(p.Leu1366Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 1,613,254 control chromosomes in the GnomAD database, including 29,962 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (5950 hom., cov: 32)
  • Exomes 𝑓: 0.17 (24012 hom.)
• Consequence: FANCD2 NM_001018115.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.97
• Publications: 30 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]

FANCD2OS (HGNC:28623): (FANCD2 opposite strand) This gene encodes a conserved protein of unknown function. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 3-10096385-T-G is Benign according to our data. Variant chr3-10096385-T-G is described in ClinVar as Benign. ClinVar VariationId is 257081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.97 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.457 is higher than 0.05.

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.4098T>G	p.Leu1366Leu	synonymous	Exon 42 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.4098T>G	p.Leu1366Leu	synonymous	Exon 42 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.4059T>G	p.Leu1353Leu	synonymous	Exon 41 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.4098T>G	p.Leu1366Leu	synonymous	Exon 42 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.4098T>G	p.Leu1366Leu	synonymous	Exon 42 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.4098T>G	p.Leu1366Leu	synonymous	Exon 42 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36745 AN: 152002 Hom.: 5942 Cov.: 32

Gnomad AFR AF: 0.463

Gnomad AMI AF: 0.270

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0896

Gnomad SAS AF: 0.202

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.207

GnomAD2 exomes AF: 0.181 AC: 45403 AN: 251422 AF XY: 0.178

Gnomad AFR exome AF: 0.478

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.159

Gnomad EAS exome AF: 0.0893

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.173 AC: 252509 AN: 1461134 Hom.: 24012 Cov.: 33 AF XY: 0.173 AC XY: 125520 AN XY: 726916

African (AFR) AF: 0.474 AC: 15861 AN: 33454

American (AMR) AF: 0.186 AC: 8306 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 4100 AN: 26134

East Asian (EAS) AF: 0.0760 AC: 3015 AN: 39696

South Asian (SAS) AF: 0.210 AC: 18081 AN: 86238

European-Finnish (FIN) AF: 0.123 AC: 6591 AN: 53420

Middle Eastern (MID) AF: 0.172 AC: 993 AN: 5768

European-Non Finnish (NFE) AF: 0.166 AC: 184615 AN: 1111342

Other (OTH) AF: 0.181 AC: 10947 AN: 60358

GnomAD4 genome AF: 0.242 AC: 36782 AN: 152120 Hom.: 5950 Cov.: 32 AF XY: 0.236 AC XY: 17572 AN XY: 74382

African (AFR) AF: 0.463 AC: 19198 AN: 41478

American (AMR) AF: 0.173 AC: 2646 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3470

East Asian (EAS) AF: 0.0894 AC: 463 AN: 5178

South Asian (SAS) AF: 0.202 AC: 974 AN: 4816

European-Finnish (FIN) AF: 0.116 AC: 1232 AN: 10596

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

European-Non Finnish (NFE) AF: 0.162 AC: 11026 AN: 67990

Other (OTH) AF: 0.207 AC: 436 AN: 2110

Alfa AF: 0.201 Hom.: 2921

Bravo AF: 0.258

Asia WGS AF: 0.147 AC: 513 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	-0.51
CADD	Benign	4.2
DANN	Benign	0.85
PhyloP100		2.0
Mutation Taster		=95/5	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: rs2272125; hg19: chr3-10138069; COSMIC: COSV55037985; COSMIC: COSV55037985;