17-30249111-T-C

Position:

• chr17-30249111-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000386.4(BLMH):​c.1274A>G​(p.Asp425Gly) variant causes a missense change involving the alteration of a 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: 7.58

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BLMH	NM_000386.4	c.1274A>G	p.Asp425Gly	missense_variant	12/12	ENST00000261714.11	NP_000377.1
LOC105371720	XR_001752824.2	n.892-676T>C		intron_variant, non_coding_transcript_variant
LOC105371720	XR_007065695.1	n.756-676T>C		intron_variant, non_coding_transcript_variant
LOC105371720	XR_007065698.1	n.756-2963T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BLMH	ENST00000261714.11	c.1274A>G	p.Asp425Gly	missense_variant	12/12	1	NM_000386.4	ENSP00000261714	P1
	ENST00000577420.1	n.61-2963T>C		intron_variant, non_coding_transcript_variant		3
BLMH	ENST00000578795.1	n.1173A>G		non_coding_transcript_exon_variant	1/1
BLMH	ENST00000578090.5	c.*948A>G		3_prime_UTR_variant, NMD_transcript_variant	11/11	2		ENSP00000462353

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 17, 2024

The c.1274A>G (p.D425G) alteration is located in exon 12 (coding exon 12) of the BLMH gene. This alteration results from a A to G substitution at nucleotide position 1274, causing the aspartic acid (D) at amino acid position 425 to be replaced by a glycine (G). 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	0.53
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.051	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.66		Loss of catalytic residue at D425 (P = 0.0322);
MVP		0.81
MPC		1.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.98
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-28576129;