chr3-10064855-C-G

Position:

chr3-10064855-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001018115.3(FANCD2):c.2148C>G(p.Thr716=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,613,540 control chromosomes in the GnomAD database, including 92 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T716T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0094 ( 8 hom., cov: 32)

Exomes 𝑓: 0.012 ( 84 hom. )

Consequence

FANCD2
NM_001018115.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.737

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 3-10064855-C-G is Benign according to our data. Variant chr3-10064855-C-G is described in ClinVar as [Benign]. Clinvar id is 241734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10064855-C-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.737 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0094 (1432/152286) while in subpopulation NFE AF= 0.0148 (1005/68020). AF 95% confidence interval is 0.014. There are 8 homozygotes in gnomad4. There are 652 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCD2	NM_001018115.3 linkuse as main transcript	c.2148C>G	p.Thr716=	synonymous_variant	23/44	ENST00000675286.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCD2	ENST00000675286.1 linkuse as main transcript	c.2148C>G	p.Thr716=	synonymous_variant	23/44		NM_001018115.3	P2	Q9BXW9-2

Frequencies

GnomAD3 genomes

AF:

0.00941

AC:

1432

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00258

Gnomad AMI

AF:

0.112

Gnomad AMR

AF:

0.00707

Gnomad ASJ

AF:

0.00979

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00601

Gnomad FIN

AF:

0.00255

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.00957

GnomAD3 exomes

AF:

0.00987

AC:

2478

AN:

251072

Hom.:

AF XY:

0.0101

AC XY:

1365

AN XY:

135734

show subpopulations

Gnomad AFR exome

AF:

0.00198

Gnomad AMR exome

AF:

0.00564

Gnomad ASJ exome

AF:

0.00804

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00758

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.0156

Gnomad OTH exome

AF:

0.00996

GnomAD4 exome

AF:

0.0123

AC:

18024

AN:

1461254

Hom.:

Cov.:

AF XY:

0.0123

AC XY:

8929

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00173

Gnomad4 AMR exome

AF:

0.00611

Gnomad4 ASJ exome

AF:

0.00980

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00746

Gnomad4 FIN exome

AF:

0.00487

Gnomad4 NFE exome

AF:

0.0143

Gnomad4 OTH exome

AF:

0.0107

GnomAD4 genome

AF:

0.00940

AC:

1432

AN:

152286

Hom.:

Cov.:

AF XY:

0.00875

AC XY:

652

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00257

Gnomad4 AMR

AF:

0.00706

Gnomad4 ASJ

AF:

0.00979

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00601

Gnomad4 FIN

AF:

0.00255

Gnomad4 NFE

AF:

0.0148

Gnomad4 OTH

AF:

0.00947

Alfa

AF:

0.0119

Hom.:

Bravo

AF:

0.00964

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0138

EpiControl

AF:

0.0144

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	FANCD2: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fanconi anemia complementation group D2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Fanconi anemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.3

DANN

Benign

0.37

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over