rs746218707

Positions:

• chr15-90794310-T-C

Variant summary

Our verdict is Pathogenic. Variant got 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:2 U:1
• Conservation: PhyloP100: 7.80

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 Pathogenic. Variant got 18 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity BLM_HUMAN there are 5 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-C is described in ClinVar as [Pathogenic]. Clinvar id is 42078.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 id is 549904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BLM	NM_000057.4	c.3163T>C	p.Cys1055Arg	missense_variant	16/22	ENST00000355112.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BLM	ENST00000355112.8	c.3163T>C	p.Cys1055Arg	missense_variant	16/22	1	NM_000057.4	P2

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

Gnomad4 AFR AF: 0.00

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bloom syndrome Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 07, 2023	- -
Uncertain significance, flagged submission	clinical testing	Counsyl	Dec 24, 2017	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

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;.
MutationTaster	Benign	1.0	D;D
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
Polyphen		1.0	D;.
Vest4		0.84
MutPred		0.93		Gain of disorder (P = 0.013);Gain of disorder (P = 0.013);
MVP		0.94
MPC		0.64
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.94

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: rs746218707; hg19: chr15-91337540;