NM_001018115.3:c.2702G>T

Variant names:

• chr3-10073349-G-T
• rs35495399
• NM_001018115.3:c.2702G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):​c.2702G>T​(p.Gly901Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0299 in 1,611,202 control chromosomes in the GnomAD database, including 860 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G901S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.022 (61 hom., cov: 32)
  • Exomes 𝑓: 0.031 (799 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.64
• Publications: 18 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039370656).
• BP6: Variant 3-10073349-G-T is Benign according to our data. Variant chr3-10073349-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0221 (3364/152232) while in subpopulation NFE AF = 0.0346 (2353/68032). AF 95% confidence interval is 0.0334. There are 61 homozygotes in GnomAd4. There are 1590 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 AR gene

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.2702G>T	p.Gly901Val	missense	Exon 28 of 44	NP_001018125.1
	FANCD2	NM_033084.6		c.2702G>T	p.Gly901Val	missense	Exon 28 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.2702G>T	p.Gly901Val	missense	Exon 28 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.2702G>T	p.Gly901Val	missense	Exon 28 of 44	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.2702G>T	p.Gly901Val	missense	Exon 28 of 43	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.2702G>T	p.Gly901Val	missense	Exon 28 of 44	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3364 AN: 152114 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00592

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0249

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0218 AC: 5486 AN: 251444 AF XY: 0.0213

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.0176

Gnomad ASJ exome AF: 0.0217

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0230

Gnomad NFE exome AF: 0.0330

Gnomad OTH exome AF: 0.0280

GnomAD4 exome AF: 0.0307 AC: 44743 AN: 1458970 Hom.: 799 Cov.: 30 AF XY: 0.0300 AC XY: 21751 AN XY: 725924

African (AFR) AF: 0.00470 AC: 157 AN: 33424

American (AMR) AF: 0.0183 AC: 819 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 616 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00490 AC: 422 AN: 86204

European-Finnish (FIN) AF: 0.0230 AC: 1226 AN: 53406

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5762

European-Non Finnish (NFE) AF: 0.0359 AC: 39809 AN: 1109380

Other (OTH) AF: 0.0279 AC: 1680 AN: 60280

GnomAD4 genome AF: 0.0221 AC: 3364 AN: 152232 Hom.: 61 Cov.: 32 AF XY: 0.0214 AC XY: 1590 AN XY: 74426

African (AFR) AF: 0.00590 AC: 245 AN: 41528

American (AMR) AF: 0.0234 AC: 358 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0222 AC: 77 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.0249 AC: 264 AN: 10586

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.0346 AC: 2353 AN: 68032

Other (OTH) AF: 0.0180 AC: 38 AN: 2112

Alfa AF: 0.0299 Hom.: 286

Bravo AF: 0.0214

TwinsUK AF: 0.0364 AC: 135

ALSPAC AF: 0.0353 AC: 136

ESP6500AA AF: 0.00817 AC: 36

ESP6500EA AF: 0.0347 AC: 298

ExAC AF: 0.0220 AC: 2673

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0277

EpiControl AF: 0.0308

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.081	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.041
Sift	Benign	0.21	T
Sift4G	Benign	0.093	T
Polyphen		0.13	B
Vest4		0.20
MPC		0.22
ClinPred		0.022	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.15
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: rs35495399; hg19: chr3-10115033; COSMIC: COSV55033803;