chr3-10049365-C-T

Variant names:

• chr3-10049365-C-T
• rs35557429
• NM_001018115.3:c.1414-9C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001018115.3(FANCD2):​c.1414-9C>T variant causes a 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 intron
• Scores: Splicing: ADA: 0.00009997
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0450
• Publications: 7 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 -16 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 VariationId is 241731.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 265 AR gene

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.1414-9C>T		intron	N/A	NP_001018125.1
	FANCD2	NM_033084.6		c.1414-9C>T		intron	N/A	NP_149075.2
	FANCD2	NM_001374254.1		c.1414-9C>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.1414-9C>T		intron	N/A	ENSP00000502379.1
	FANCD2	ENST00000287647.7	TSL:1	c.1414-9C>T		intron	N/A	ENSP00000287647.3
	FANCD2	ENST00000419585.5	TSL:1	c.1414-9C>T		intron	N/A	ENSP00000398754.1

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

GnomAD2 exomes AF: 0.0425 AC: 9170 AN: 215894 AF XY: 0.0403

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.0444

Gnomad ASJ exome AF: 0.0339

Gnomad EAS exome AF: 0.0162

Gnomad FIN exome AF: 0.0126

Gnomad NFE exome AF: 0.0344

Gnomad OTH exome AF: 0.0427

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

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

African (AFR) AF: 0.191 AC: 5026 AN: 26376

American (AMR) AF: 0.0616 AC: 2386 AN: 38760

Ashkenazi Jewish (ASJ) AF: 0.0698 AC: 1594 AN: 22824

East Asian (EAS) AF: 0.0266 AC: 1002 AN: 37712

South Asian (SAS) AF: 0.0836 AC: 6147 AN: 73520

European-Finnish (FIN) AF: 0.0422 AC: 2054 AN: 48722

Middle Eastern (MID) AF: 0.0611 AC: 304 AN: 4976

European-Non Finnish (NFE) AF: 0.0597 AC: 56005 AN: 938822

Other (OTH) AF: 0.0725 AC: 3762 AN: 51856

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

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

African (AFR) AF: 0.166 AC: 5228 AN: 31478

American (AMR) AF: 0.0728 AC: 985 AN: 13532

Ashkenazi Jewish (ASJ) AF: 0.0729 AC: 220 AN: 3018

East Asian (EAS) AF: 0.0347 AC: 171 AN: 4934

South Asian (SAS) AF: 0.0859 AC: 359 AN: 4180

European-Finnish (FIN) AF: 0.0519 AC: 495 AN: 9538

Middle Eastern (MID) AF: 0.0876 AC: 24 AN: 274

European-Non Finnish (NFE) AF: 0.0751 AC: 4400 AN: 58554

Other (OTH) AF: 0.0716 AC: 128 AN: 1788

⚠️ 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: 0.180 Hom.: 752

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fanconi anemia Benign:1

Dec 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.8
DANN	Benign	0.40
PhyloP100		0.045
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs35557429; hg19: chr3-10091049; COSMIC: COSV55036272; COSMIC: COSV55036272;