17-80995727-T-C

Position:

• chr17-80995727-T-C

Variant summary

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

The NM_024591.5(CHMP6):​c.317T>C​(p.Phe106Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,738 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP6 NM_024591.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.52

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=0.29454347).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.317T>C	p.Phe106Ser	missense_variant	4/8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.317T>C	p.Phe106Ser	missense_variant	4/7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9	c.317T>C	p.Phe106Ser	missense_variant	4/8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572778.5	c.254T>C	p.Phe85Ser	missense_variant	3/6	2		ENSP00000461098.1
CHMP6	ENST00000571457.1	c.191T>C	p.Phe64Ser	missense_variant	3/7	3		ENSP00000461238.1
CHMP6	ENST00000572525.5	c.59T>C	p.Phe20Ser	missense_variant	4/8	3		ENSP00000460389.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461738 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727182

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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

Jan 23, 2024

The c.317T>C (p.F106S) alteration is located in exon 4 (coding exon 4) of the CHMP6 gene. This alteration results from a T to C substitution at nucleotide position 317, causing the phenylalanine (F) at amino acid position 106 to be replaced by a serine (S). 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	0.098
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	19
DANN	Benign	0.86
DEOGEN2	Benign	0.15	T;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.86	D;T;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.58	.;N;.;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.34	.;N;.;.
REVEL	Benign	0.23
Sift	Benign	0.48	.;T;.;.
Sift4G	Benign	0.51	T;T;T;T
Polyphen		0.0	.;B;.;.
Vest4		0.41
MutPred		0.46		.;Gain of disorder (P = 0.0022);.;.;
MVP		0.51
MPC		0.12
ClinPred		0.31	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.59

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: rs969096884; hg19: chr17-78969527;