15-90747402-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000057.4(BLM):c.10G>A(p.Val4Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -0.408

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08381483).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.10G>A	p.Val4Ile	missense_variant	2/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.10G>A	p.Val4Ile	missense_variant	2/22	1	NM_000057.4	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000408 AC: 1 AN: 245122 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 132402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000909

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456716 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724304

Gnomad4 AFR exome AF: 0.00

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Bloom syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	May 29, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 4 of the BLM protein (p.Val4Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 1051649). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 26, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	8.4
Dann	Benign	0.92
DEOGEN2	Benign	0.048	T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.74	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.084	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.060	N;N
REVEL	Benign	0.033
Sift	Benign	0.18	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0050	B;.
Vest4		0.10
MutPred		0.23		Gain of catalytic residue at L9 (P = 0.0848);Gain of catalytic residue at L9 (P = 0.0848);
MVP		0.55
MPC		0.075
ClinPred		0.038	T
GERP RS		-4.1
Varity_R		0.031
gMVP		0.017

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1466614215; hg19: chr15-91290632;