17-30291395-G-A

Variant names:

• chr17-30291395-G-A
• rs1597670127
• NM_000386.4:c.127C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000386.4(BLMH):​c.127C>T​(p.Arg43Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BLMH NM_000386.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.05

Genes affected

BLMH (HGNC:1059): (bleomycin hydrolase) Bleomycin hydrolase (BMH) is a cytoplasmic cysteine peptidase that is highly conserved through evolution; however, the only known activity of the enzyme is metabolic inactivation of the glycopeptide bleomycin (BLM), an essential component of combination chemotherapy regimens for cancer. The protein contains the signature active site residues of the cysteine protease papain superfamily. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BLMH	NM_000386.4	c.127C>T	p.Arg43Trp	missense_variant	Exon 2 of 12	ENST00000261714.11	NP_000377.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BLMH	ENST00000261714.11	c.127C>T	p.Arg43Trp	missense_variant	Exon 2 of 12	1	NM_000386.4	ENSP00000261714.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 22, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.127C>T (p.R43W) alteration is located in exon 2 (coding exon 2) of the BLMH gene. This alteration results from a C to T substitution at nucleotide position 127, causing the arginine (R) at amino acid position 43 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Benign	0.97
DEOGEN2	Uncertain	0.58	D;.
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.79	D;D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.2	D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.84
MVP		0.68
MPC		0.96
ClinPred		1.0	D
GERP RS		2.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.80
gMVP		0.63

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: rs1597670127; hg19: chr17-28618413;