rs746218707

Variant names:

• chr15-90794310-T-C
• rs746218707
• NM_000057.4:c.3163T>C

Your query was ambiguous. Multiple possible variants found:

• chr15-90794310-T-C
• chr15-90794310-T-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000057.4(BLM):​c.3163T>C​(p.Cys1055Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1055Y) has been classified as Likely pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: BLM NM_000057.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1
• Conservation: PhyloP100: 7.80
• Publications: 2 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

ENSG00000300894 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a helix (size 3) in uniprot entity BLM_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000057.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr15-90794311-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 803137.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 15-90794310-T-C is Pathogenic according to our data. Variant chr15-90794310-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 549904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLM	NM_000057.4	c.3163T>C	p.Cys1055Arg	missense_variant	Exon 16 of 22	ENST00000355112.8	NP_000048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLM	ENST00000355112.8	c.3163T>C	p.Cys1055Arg	missense_variant	Exon 16 of 22	1	NM_000057.4	ENSP00000347232.3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152168 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000361 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:2 Uncertain:1

Dec 24, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Mar 07, 2023

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: BLM c.3163T>C (p.Cys1055Arg) results in a non-conservative amino acid change located in the ATP-dependent DNA helicase RecQ, zinc-binding domain (IPR032284) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248860 control chromosomes. c.3163T>C has been reported in the literature in the presumed compound heterozygous state in at least 1 individual affected with Bloom Syndrome (example, German_2007). These data do not allow any conclusion about variant significance. At least 2 different variants affecting the same codon have been classified as likely pathogenic/pathogenic by our lab or other labs in ClinVar (c.3164G>C, p.Cys1055Ser; c.3163T>G p.Cys1055Gly), supporting the critical relevance of codon 1055 to BLM protein function. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported for this variant, p.Cys1055Arg. The following publication has been ascertained in the context of this evaluation (PMID: 17407155). ClinVar contains an entry for this variant (Variation ID: 549904). Based on the evidence outlined above, the variant was classified as likely pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 22, 2021

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C1055R variant (also known as c.3163T>C), located in coding exon 15 of the BLM gene, results from a T to C substitution at nucleotide position 3163. The cysteine at codon 1055 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in one patient with Bloom syndrome who also carried c.2098C>T (German J et al. Hum Mutat, 2007 Aug;28:743-53). Another alteration at the same codon, p.C1055S (c.3164G>C), has been reported in the literature in both a homozygous and compound heterozygous state in individuals with Bloom syndrome (Ellis NA et al. Cell, 1995 Nov;83:655-66; German J et al. Hum. Mutat., 2007 Aug;28:743-53; Montenegro MM et al. Mol Genet Genomic Med, 2020 04;8:e1133). Functional studies of p.C1055S have also demonstrated that this alteration causes reduced BLM protein expression and lacks detectable helicase and DNA-dependent ATPase activities, which are essential for wild-type interaction of BLM with tp53 in the DNA damage response pathway (Wang XW et al. J. Biol. Chem., 2001 Aug;276:32948-55; Neff NF et al. Mol. Biol. Cell, 1999 Mar;10:665-76). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	4.5	H;.
PhyloP100		7.8
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-11	D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0	D;D
Vest4		0.84
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.94
Mutation Taster		=1/99	disease causing

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

Other links and lift over

dbSNP: rs746218707; hg19: chr15-91337540;