rs36084488

Variant names:

• chr3-10032962-G-C
• rs36084488
• NM_001018115.3:c.195G>C

Your query was ambiguous. Multiple possible variants found:

• chr3-10032962-G-C
• chr3-10032962-G-A

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.195G>C​(p.Gln65His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,575,196 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0070 (20 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (11 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10 O:1
• Conservation: PhyloP100: 1.06
• Publications: 9 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=0.008865625).
• BP6: Variant 3-10032962-G-C is Benign according to our data. Variant chr3-10032962-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00697 (1062/152266) while in subpopulation AFR AF = 0.0225 (936/41536). AF 95% confidence interval is 0.0213. There are 20 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 20 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.195G>C	p.Gln65His	missense	Exon 3 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.195G>C	p.Gln65His	missense	Exon 3 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.195G>C	p.Gln65His	missense	Exon 3 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.195G>C	p.Gln65His	missense	Exon 3 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.195G>C	p.Gln65His	missense	Exon 3 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.195G>C	p.Gln65His	missense	Exon 3 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152148 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0226

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00268 AC: 671 AN: 250704 AF XY: 0.00252

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00129 AC: 1840 AN: 1422930 Hom.: 11 Cov.: 27 AF XY: 0.00128 AC XY: 907 AN XY: 710338

African (AFR) AF: 0.0214 AC: 699 AN: 32630

American (AMR) AF: 0.00242 AC: 108 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25890

East Asian (EAS) AF: 0.00259 AC: 102 AN: 39422

South Asian (SAS) AF: 0.00271 AC: 231 AN: 85248

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53394

Middle Eastern (MID) AF: 0.00481 AC: 27 AN: 5608

European-Non Finnish (NFE) AF: 0.000466 AC: 502 AN: 1076998

Other (OTH) AF: 0.00284 AC: 168 AN: 59082

GnomAD4 genome AF: 0.00697 AC: 1062 AN: 152266 Hom.: 20 Cov.: 32 AF XY: 0.00705 AC XY: 525 AN XY: 74452

African (AFR) AF: 0.0225 AC: 936 AN: 41536

American (AMR) AF: 0.00340 AC: 52 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00289 AC: 15 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000588 AC: 40 AN: 68026

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00153 Hom.: 2

Bravo AF: 0.00810

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0207 AC: 91

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00303 AC: 368

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.000654

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0089	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.1
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.18
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.10		Loss of helix (P = 0.079)
MVP		0.75
MPC		0.28
ClinPred		0.037	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.27
Mutation Taster		=92/8	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: rs36084488; hg19: chr3-10074646; COSMIC: COSV109418514; COSMIC: COSV109418514;