rs35557429

chr3-10049365-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):c.1414-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0946 in 127,986 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.095 (265 hom., cov: 31)
  • Exomes 𝑓: 0.063 (2996 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00009997
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0450

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=-0.84).
• BP6: Variant 3-10049365-C-T is Benign according to our data. Variant chr3-10049365-C-T is described in ClinVar as [Benign]. Clinvar id is 241731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10049365-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3	c.1414-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1	c.1414-9C>T		splice_polypyrimidine_tract_variant, intron_variant			NM_001018115.3	P2

Frequencies

GnomAD3 genomes AF: 0.0946 AC: 12098 AN: 127898 Hom.: 265 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.0732

Gnomad ASJ AF: 0.0729

Gnomad EAS AF: 0.0346

Gnomad SAS AF: 0.0850

Gnomad FIN AF: 0.0519

Gnomad MID AF: 0.0890

Gnomad NFE AF: 0.0752

Gnomad OTH AF: 0.0713

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0629 AC: 78280 AN: 1243568 Hom.: 2996 Cov.: 34 AF XY: 0.0632 AC XY: 39166 AN XY: 619370

Gnomad4 AFR exome AF: 0.191

Gnomad4 AMR exome AF: 0.0616

Gnomad4 ASJ exome AF: 0.0698

Gnomad4 EAS exome AF: 0.0266

Gnomad4 SAS exome AF: 0.0836

Gnomad4 FIN exome AF: 0.0422

Gnomad4 NFE exome AF: 0.0597

Gnomad4 OTH exome AF: 0.0725

GnomAD4 genome AF: 0.0946 AC: 12103 AN: 127986 Hom.: 265 Cov.: 31 AF XY: 0.0892 AC XY: 5589 AN XY: 62630

Gnomad4 AFR AF: 0.166

Gnomad4 AMR AF: 0.0728

Gnomad4 ASJ AF: 0.0729

Gnomad4 EAS AF: 0.0347

Gnomad4 SAS AF: 0.0859

Gnomad4 FIN AF: 0.0519

Gnomad4 NFE AF: 0.0751

Gnomad4 OTH AF: 0.0716

Alfa AF: 0.121 Hom.: 131

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia complementation group D2 Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 23, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	1.8
Dann	Benign	0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0080
SpliceAI score (max)		0.030		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: rs35557429; hg19: chr3-10091049; COSMIC: COSV55036272; COSMIC: COSV55036272;