rs35749514

Variant names:

• chr3-10039690-G-A
• rs35749514
• NM_001018115.3:c.571-31G>A

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.571-31G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00528 in 1,613,410 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (226 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (200 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.710
• Publications: 3 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 (BayesDel_noAF=-0.5).
• BP6: Variant 3-10039690-G-A is Benign according to our data. Variant chr3-10039690-G-A is described in ClinVar as Benign. ClinVar VariationId is 257084.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0972 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	NM_001018115.3	MANE Select	c.571-31G>A		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.571-31G>A		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.571-31G>A		intron	N/A	NP_001361183.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCD2	ENST00000675286.1	MANE Select	c.571-31G>A		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.571-31G>A		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.571-31G>A		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4351 AN: 152038 Hom.: 223 Cov.: 31

Gnomad AFR AF: 0.0997

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.00719 AC: 1806 AN: 251292 AF XY: 0.00526

Gnomad AFR exome AF: 0.100

Gnomad AMR exome AF: 0.00387

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00284 AC: 4154 AN: 1461254 Hom.: 200 Cov.: 31 AF XY: 0.00251 AC XY: 1824 AN XY: 726944

African (AFR) AF: 0.0993 AC: 3323 AN: 33452

American (AMR) AF: 0.00467 AC: 209 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86138

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00489 AC: 28 AN: 5724

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111634

Other (OTH) AF: 0.00726 AC: 438 AN: 60356

GnomAD4 genome AF: 0.0287 AC: 4362 AN: 152156 Hom.: 226 Cov.: 31 AF XY: 0.0282 AC XY: 2099 AN XY: 74410

African (AFR) AF: 0.0997 AC: 4137 AN: 41490

American (AMR) AF: 0.0104 AC: 159 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67996

Other (OTH) AF: 0.0232 AC: 49 AN: 2112

Alfa AF: 0.0141 Hom.: 35

Bravo AF: 0.0330

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia complementation group D2 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Apr 03, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.2
DANN	Benign	0.76
PhyloP100		0.71
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35749514; hg19: chr3-10081374; COSMIC: COSV55034949;