3-10078233-T-C

Variant names:

• chr3-10078233-T-C
• rs6805869
• NM_001018115.3:c.2976+36T>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.2976+36T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 1,369,982 control chromosomes in the GnomAD database, including 23,785 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5016 hom., cov: 31)
  • Exomes 𝑓: 0.17 (18769 hom.)
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.354
• Publications: 14 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=-0.86).
• BP6: Variant 3-10078233-T-C is Benign according to our data. Variant chr3-10078233-T-C is described in ClinVar as Benign. ClinVar VariationId is 257077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.414 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.2976+36T>C		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.2976+36T>C		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.2976+36T>C		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.2976+36T>C		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.2976+36T>C		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.2976+36T>C		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.226 AC: 34296 AN: 151858 Hom.: 5011 Cov.: 31

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.156

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.0658

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.194

GnomAD2 exomes AF: 0.169 AC: 42501 AN: 251368 AF XY: 0.167

Gnomad AFR exome AF: 0.433

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.158

Gnomad EAS exome AF: 0.0657

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.159

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.168 AC: 204163 AN: 1218006 Hom.: 18769 Cov.: 17 AF XY: 0.167 AC XY: 103477 AN XY: 618242

African (AFR) AF: 0.427 AC: 12230 AN: 28610

American (AMR) AF: 0.162 AC: 7199 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 3834 AN: 24578

East Asian (EAS) AF: 0.0566 AC: 2180 AN: 38496

South Asian (SAS) AF: 0.185 AC: 14998 AN: 81278

European-Finnish (FIN) AF: 0.123 AC: 6549 AN: 53164

Middle Eastern (MID) AF: 0.165 AC: 869 AN: 5252

European-Non Finnish (NFE) AF: 0.165 AC: 147191 AN: 889918

Other (OTH) AF: 0.174 AC: 9113 AN: 52360

GnomAD4 genome AF: 0.226 AC: 34330 AN: 151976 Hom.: 5016 Cov.: 31 AF XY: 0.220 AC XY: 16369 AN XY: 74324

African (AFR) AF: 0.419 AC: 17366 AN: 41400

American (AMR) AF: 0.156 AC: 2376 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 523 AN: 3472

East Asian (EAS) AF: 0.0658 AC: 340 AN: 5168

South Asian (SAS) AF: 0.165 AC: 794 AN: 4814

European-Finnish (FIN) AF: 0.116 AC: 1226 AN: 10584

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11015 AN: 67960

Other (OTH) AF: 0.194 AC: 408 AN: 2106

Alfa AF: 0.195 Hom.: 667

Bravo AF: 0.240

Asia WGS AF: 0.126 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group D2 Benign:2

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Feb 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

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	-0.86
CADD	Benign	5.9
DANN	Benign	0.64
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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: rs6805869; hg19: chr3-10119917; COSMIC: COSV55037214; COSMIC: COSV55037214;