rs414634

Variant names:

• chr15-90813023-A-C
• rs414634
• NM_000057.4:c.4076+1617A>C

Your query was ambiguous. Multiple possible variants found:

• chr15-90813023-A-C
• chr15-90813023-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000057.4(BLM):​c.4076+1617A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.735 in 152,056 control chromosomes in the GnomAD database, including 41,368 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.74 (41368 hom., cov: 31)
• Consequence: BLM NM_000057.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.08
• Publications: 18 publications found

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]

BLM Gene-Disease associations (from GenCC):

• Bloom syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine, Orphanet, Genomics England PanelApp, ClinGen
• osteosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary nonpolyposis colon cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics

ENSG00000287061 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.4076+1617A>C		intron_variant	Intron 21 of 21	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.4076+1617A>C		intron_variant	Intron 21 of 21	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.735 AC: 111727 AN: 151938 Hom.: 41318 Cov.: 31

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.809

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.719

Gnomad EAS AF: 0.843

Gnomad SAS AF: 0.685

Gnomad FIN AF: 0.732

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.700

Gnomad OTH AF: 0.715

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.735 AC: 111836 AN: 152056 Hom.: 41368 Cov.: 31 AF XY: 0.736 AC XY: 54714 AN XY: 74308

African (AFR) AF: 0.771 AC: 31990 AN: 41466

American (AMR) AF: 0.783 AC: 11965 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.719 AC: 2495 AN: 3470

East Asian (EAS) AF: 0.843 AC: 4362 AN: 5174

South Asian (SAS) AF: 0.685 AC: 3301 AN: 4816

European-Finnish (FIN) AF: 0.732 AC: 7727 AN: 10558

Middle Eastern (MID) AF: 0.653 AC: 192 AN: 294

European-Non Finnish (NFE) AF: 0.700 AC: 47557 AN: 67970

Other (OTH) AF: 0.716 AC: 1511 AN: 2110

Alfa AF: 0.711 Hom.: 169587

Bravo AF: 0.744

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.13
DANN	Benign	0.33
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs414634; hg19: chr15-91356253;