Genetic Variant BLM:p.Ser778Phe (chr15-90769158-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000057.4(BLM):c.2333C>T(p.Ser778Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S778C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

BLM
NM_000057.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.24

Publications

0 publications found

Variant links:

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

BLM links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.843

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000057.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLM	NM_000057.4	MANE Select	c.2333C>T	p.Ser778Phe	missense	Exon 11 of 22	NP_000048.1
BLM	NM_001287246.2		c.2333C>T	p.Ser778Phe	missense	Exon 12 of 23	NP_001274175.1
BLM	NM_001287247.2		c.2333C>T	p.Ser778Phe	missense	Exon 11 of 20	NP_001274176.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BLM	ENST00000355112.8	TSL:1 MANE Select	c.2333C>T	p.Ser778Phe	missense	Exon 11 of 22	ENSP00000347232.3
BLM	ENST00000560509.5	TSL:1	c.2333C>T	p.Ser778Phe	missense	Exon 11 of 20	ENSP00000454158.1
BLM	ENST00000559724.5	TSL:1	n.*1257C>T		non_coding_transcript_exon	Exon 11 of 22	ENSP00000453359.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.17

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.44

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.84

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.8

PhyloP100

4.2

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-5.0

REVEL

Pathogenic

0.68

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.41

Vest4

0.86

MutPred

0.54

Loss of helix (P = 0.0093)

MVP

0.91

MPC

0.49

ClinPred

0.98

GERP RS

5.3

Varity_R

0.87

gMVP

0.85

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over