3-10028652-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001018115.3(FANCD2):c.-6G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00393 in 1,613,792 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (77 hom.)
• Consequence: FANCD2 NM_001018115.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00200

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 3-10028652-G-C is Benign according to our data. Variant chr3-10028652-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 342253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00357 (544/152282) while in subpopulation EAS AF= 0.0312 (162/5188). AF 95% confidence interval is 0.0273. There are 8 homozygotes in gnomad4. There are 319 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.-6G>C		5_prime_UTR_variant	2/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.-6G>C		5_prime_UTR_variant	2/44		NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.00358 AC: 545 AN: 152164 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00642

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0313

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00652 AC: 1639 AN: 251400 Hom.: 25 AF XY: 0.00732 AC XY: 995 AN XY: 135870

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0264

Gnomad SAS exome AF: 0.0241

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00396 AC: 5792 AN: 1461510 Hom.: 77 Cov.: 30 AF XY: 0.00456 AC XY: 3314 AN XY: 727092

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00440

Gnomad4 ASJ exome AF: 0.000727

Gnomad4 EAS exome AF: 0.0343

Gnomad4 SAS exome AF: 0.0252

Gnomad4 FIN exome AF: 0.000131

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00571

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152282 Hom.: 8 Cov.: 32 AF XY: 0.00428 AC XY: 319 AN XY: 74476

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0312

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00181 Hom.: 0

Bravo AF: 0.00269

Asia WGS AF: 0.0400 AC: 141 AN: 3478

EpiCase AF: 0.00224

EpiControl AF: 0.00231

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	6.5
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs3732974; hg19: chr3-10070336; COSMIC: COSV104599157; COSMIC: COSV104599157;