17-80995711-A-T

Position:

• chr17-80995711-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024591.5(CHMP6):​c.301A>T​(p.Met101Leu) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: CHMP6 NM_024591.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

Genes affected

CHMP6 (HGNC:25675): (charged multivesicular body protein 6) This gene encodes a member of the chromatin-modifying protein/charged multivesicular body protein family. Proteins in this family are part of the ESCRT-III (endosomal sorting complex required for transport III) which degrades surface receptors, and in biosynthesis of endosomes. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0727365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.301A>T	p.Met101Leu	missense_variant	4/8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.301A>T	p.Met101Leu	missense_variant	4/7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9	c.301A>T	p.Met101Leu	missense_variant	4/8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572778.5	c.238A>T	p.Met80Leu	missense_variant	3/6	2		ENSP00000461098.1
CHMP6	ENST00000571457.1	c.175A>T	p.Met59Leu	missense_variant	3/7	3		ENSP00000461238.1
CHMP6	ENST00000572525.5	c.43A>T	p.Met15Leu	missense_variant	4/8	3		ENSP00000460389.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

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

May 14, 2024

The c.301A>T (p.M101L) alteration is located in exon 4 (coding exon 4) of the CHMP6 gene. This alteration results from a A to T substitution at nucleotide position 301, causing the methionine (M) at amino acid position 101 to be replaced by a leucine (L). 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	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.16	T;T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.76
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.83	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.073	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.79	.;N;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.090	.;N;.;.
REVEL	Benign	0.15
Sift	Benign	1.0	.;T;.;.
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.28
MutPred		0.49		.;Gain of catalytic residue at M101 (P = 0.0401);.;.;
MVP		0.28
MPC		0.062
ClinPred		0.088	T
GERP RS		-0.61
Varity_R		0.031
gMVP		0.39

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-78969511;