3-10035158-CTT-C

Position:

• chr3-10035158-CTT-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001018115.3(FANCD2):​c.378-6_378-5del 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 0.194 in 1,433,924 control chromosomes in the GnomAD database, including 27,271 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.23 (4999 hom., cov: 25)
  • Exomes 𝑓: 0.19 (22272 hom.)
• Consequence: FANCD2 NM_001018115.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.334

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 -16 ACMG points.

• BP6: Variant 3-10035158-CTT-C is Benign according to our data. Variant chr3-10035158-CTT-C is described in ClinVar as [Likely_benign]. Clinvar id is 342255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10035158-CTT-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.417 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FANCD2	NM_001018115.3	c.378-6_378-5del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000675286.1	NP_001018125.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FANCD2	ENST00000675286.1	c.378-6_378-5del		splice_polypyrimidine_tract_variant, intron_variant			NM_001018115.3	ENSP00000502379	P2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34235 AN: 149558 Hom.: 4993 Cov.: 25

Gnomad AFR AF: 0.423

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.152

Gnomad EAS AF: 0.0663

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.144

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.233 AC: 42195 AN: 181326 Hom.: 4329 AF XY: 0.230 AC XY: 22437 AN XY: 97648

Gnomad AFR exome AF: 0.474

Gnomad AMR exome AF: 0.235

Gnomad ASJ exome AF: 0.235

Gnomad EAS exome AF: 0.0966

Gnomad SAS exome AF: 0.253

Gnomad FIN exome AF: 0.182

Gnomad NFE exome AF: 0.213

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.190 AC: 243884 AN: 1284262 Hom.: 22272 AF XY: 0.189 AC XY: 121061 AN XY: 639418

Gnomad4 AFR exome AF: 0.455

Gnomad4 AMR exome AF: 0.182

Gnomad4 ASJ exome AF: 0.180

Gnomad4 EAS exome AF: 0.0677

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.187

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.229 AC: 34271 AN: 149662 Hom.: 4999 Cov.: 25 AF XY: 0.223 AC XY: 16321 AN XY: 73102

Gnomad4 AFR AF: 0.422

Gnomad4 AMR AF: 0.158

Gnomad4 ASJ AF: 0.152

Gnomad4 EAS AF: 0.0663

Gnomad4 SAS AF: 0.166

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.197

Alfa AF: 0.112 Hom.: 220

Bravo AF: 0.240

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 02, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 09, 2019	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 17, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs55973240; hg19: chr3-10076842;