rs36070315

Variant names:

• chr3-10063832-A-C
• rs36070315
• NM_001018115.3:c.1868A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.1868A>C​(p.Gln623Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0041 in 1,614,084 control chromosomes in the GnomAD database, including 141 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (113 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (28 hom.)
• Consequence: FANCD2 NM_001018115.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 6.76
• Publications: 8 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=0.004644096).
• BP6: Variant 3-10063832-A-C is Benign according to our data. Variant chr3-10063832-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0767 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.1868A>C	p.Gln623Pro	missense	Exon 21 of 44	NP_001018125.1	Q9BXW9-2
	FANCD2	NM_033084.6		c.1868A>C	p.Gln623Pro	missense	Exon 21 of 43	NP_149075.2
	FANCD2	NM_001374254.1		c.1868A>C	p.Gln623Pro	missense	Exon 21 of 42	NP_001361183.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.1868A>C	p.Gln623Pro	missense	Exon 21 of 44	ENSP00000502379.1	Q9BXW9-2
	FANCD2	ENST00000287647.7	TSL:1	c.1868A>C	p.Gln623Pro	missense	Exon 21 of 43	ENSP00000287647.3	Q9BXW9-1
	FANCD2	ENST00000419585.5	TSL:1	c.1868A>C	p.Gln623Pro	missense	Exon 21 of 44	ENSP00000398754.1	Q9BXW9-2

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3456 AN: 152162 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.0791

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00845

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.00548 AC: 1377 AN: 251436 AF XY: 0.00394

Gnomad AFR exome AF: 0.0767

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00216 AC: 3156 AN: 1461804 Hom.: 28 Cov.: 33 AF XY: 0.00187 AC XY: 1357 AN XY: 727194

African (AFR) AF: 0.0762 AC: 2549 AN: 33442

American (AMR) AF: 0.00364 AC: 163 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000121 AC: 134 AN: 1111966

Other (OTH) AF: 0.00484 AC: 292 AN: 60392

GnomAD4 genome AF: 0.0227 AC: 3461 AN: 152280 Hom.: 113 Cov.: 32 AF XY: 0.0221 AC XY: 1643 AN XY: 74474

African (AFR) AF: 0.0790 AC: 3280 AN: 41520

American (AMR) AF: 0.00843 AC: 129 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68030

Other (OTH) AF: 0.0185 AC: 39 AN: 2112

Alfa AF: 0.00557 Hom.: 26

Bravo AF: 0.0268

ESP6500AA AF: 0.0831 AC: 366

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00685 AC: 832

EpiCase AF: 0.000109

EpiControl AF: 0.000237

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 complementation group D2 (2)
-	-	2	not specified (3)
-	-	1	FANCD2-related disorder (1)
-	-	1	Fanconi anemia (1)
-	-	1	Fanconi anemia complementation group A (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	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.8
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.16
Sift	Benign	0.12	T
Sift4G	Uncertain	0.038	D
Polyphen		0.99	D
Vest4		0.58
MVP		0.82
MPC		0.51
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.58
gMVP		0.63
Mutation Taster		=97/3	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: rs36070315; hg19: chr3-10105516; COSMIC: COSV99078772; COSMIC: COSV99078772;