chr15-90798221-T-G

Position:

• chr15-90798221-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000057.4(BLM):​c.3242T>G​(p.Val1081Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,609,120 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.96

Genes affected

BLM (HGNC:1058): (BLM RecQ like helicase) The Bloom syndrome is an autosomal recessive disorder characterized by growth deficiency, microcephaly and immunodeficiency among others. It is caused by homozygous or compound heterozygous mutation in the gene encoding DNA helicase RecQ protein on chromosome 15q26. This Bloom-associated helicase unwinds a variety of DNA substrates including Holliday junction, and is involved in several pathways contributing to the maintenance of genome stability. Identification of pathogenic Bloom variants is required for heterozygote testing in at-risk families. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLM	NM_000057.4	c.3242T>G	p.Val1081Gly	missense_variant	17/22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.3242T>G	p.Val1081Gly	missense_variant	17/22	1	NM_000057.4	ENSP00000347232	P2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456934 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725022

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jul 18, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 23, 2022	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1081 of the BLM protein (p.Val1081Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BLM-related conditions. ClinVar contains an entry for this variant (Variation ID: 855691). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 23, 2023

The p.V1081G variant (also known as c.3242T>G), located in coding exon 16 of the BLM gene, results from a T to G substitution at nucleotide position 3242. The valine at codon 1081 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.87	T
MutationAssessor	Pathogenic	2.9	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.022	D;D
Sift4G	Benign	0.15	T;D
Polyphen		0.51	P;.
Vest4		0.62
MutPred		0.58		Loss of stability (P = 0.0255);Loss of stability (P = 0.0255);
MVP		0.83
MPC		0.53
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.84
gMVP		0.88

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

Other links and lift over

dbSNP: rs762716289; hg19: chr15-91341451;