rs3864015

Variant names:

• chr3-10064460-C-T
• rs3864015
• NM_001018115.3:c.2021+31C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM2 BP4_Strong BP6_Very_Strong

The NM_001018115.3(FANCD2):​c.2021+31C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 110,614 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (0 hom., cov: 33)
  • Exomes 𝑓: 0.082 (3 hom.)
  • Failed GnomAD Quality Control
• Consequence: FANCD2 NM_001018115.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.775
• 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 -10 ACMG points.

• PM2: Variant has high frequency in the EAS (0.174) population. However there is too low homozygotes in high coverage region: (expected more than 418, got 0).
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 3-10064460-C-T is Benign according to our data. Variant chr3-10064460-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 210979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.2021+31C>T		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.2021+31C>T		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.2021+31C>T		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.2021+31C>T		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.2021+31C>T		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.2021+31C>T		intron	N/A	ENSP00000398754.1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 13601 AN: 110536 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.108

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0981

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0756

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.0101 AC: 2204 AN: 217758 AF XY: 0.00907

Gnomad AFR exome AF: 0.0219

Gnomad AMR exome AF: 0.00798

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.0364

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00621

Gnomad OTH exome AF: 0.0111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0823 AC: 69207 AN: 840904 Hom.: 3 Cov.: 26 AF XY: 0.0792 AC XY: 33718 AN XY: 425622

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.107 AC: 2083 AN: 19428

American (AMR) AF: 0.0321 AC: 1141 AN: 35550

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 979 AN: 18662

East Asian (EAS) AF: 0.146 AC: 3785 AN: 25874

South Asian (SAS) AF: 0.0656 AC: 3773 AN: 57542

European-Finnish (FIN) AF: 0.0695 AC: 2660 AN: 38264

Middle Eastern (MID) AF: 0.104 AC: 337 AN: 3232

European-Non Finnish (NFE) AF: 0.0847 AC: 51312 AN: 606028

Other (OTH) AF: 0.0864 AC: 3137 AN: 36324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.123 AC: 13615 AN: 110614 Hom.: 0 Cov.: 33 AF XY: 0.123 AC XY: 6683 AN XY: 54198

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.178 AC: 5092 AN: 28650

American (AMR) AF: 0.104 AC: 1181 AN: 11394

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 263 AN: 2680

East Asian (EAS) AF: 0.186 AC: 628 AN: 3378

South Asian (SAS) AF: 0.133 AC: 450 AN: 3384

European-Finnish (FIN) AF: 0.0706 AC: 569 AN: 8054

Middle Eastern (MID) AF: 0.0752 AC: 17 AN: 226

European-Non Finnish (NFE) AF: 0.102 AC: 5162 AN: 50664

Other (OTH) AF: 0.119 AC: 181 AN: 1516

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.121 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 19, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Apr 01, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely 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	-0.71
CADD	Benign	5.8
DANN	Benign	0.82
PhyloP100		-0.78
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs3864015; hg19: chr3-10106144; COSMIC: COSV55045544; COSMIC: COSV55045544;