chr17-80995757-A-G

Position:

• chr17-80995757-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_024591.5(CHMP6):​c.347A>G​(p.Gln116Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: CHMP6 NM_024591.5 missense, splice_region
• Scores: Splicing: ADA: 0.8786
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.65

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31945133).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.347A>G	p.Gln116Arg	missense_variant, splice_region_variant	4/8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.347A>G	p.Gln116Arg	missense_variant, splice_region_variant	4/7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9	c.347A>G	p.Gln116Arg	missense_variant, splice_region_variant	4/8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572778.5	c.284A>G	p.Gln95Arg	missense_variant, splice_region_variant	3/6	2		ENSP00000461098.1
CHMP6	ENST00000571457.1	c.221A>G	p.Gln74Arg	missense_variant, splice_region_variant	3/7	3		ENSP00000461238.1
CHMP6	ENST00000572525.5	c.89A>G	p.Gln30Arg	missense_variant, splice_region_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

Aug 14, 2024

The c.347A>G (p.Q116R) alteration is located in exon 4 (coding exon 4) of the CHMP6 gene. This alteration results from a A to G substitution at nucleotide position 347, causing the glutamine (Q) at amino acid position 116 to be replaced by an arginine (R). 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	0.087
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;T;.;.
Eigen	Benign	-0.078
Eigen_PC	Benign	0.076
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	.;L;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	.;N;.;.
REVEL	Benign	0.14
Sift	Benign	0.30	.;T;.;.
Sift4G	Benign	0.19	T;T;D;D
Polyphen		0.0090	.;B;.;.
Vest4		0.39
MutPred		0.32		.;Gain of phosphorylation at S119 (P = 0.068);.;.;
MVP		0.69
MPC		0.072
ClinPred		0.74	D
GERP RS		4.3
Varity_R		0.19
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.69
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: chr17-78969557;