Genetic Variant CHMP6:p.Phe106Ser (chr17-80995727-T-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

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. 15/22 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.52

Publications

0 publications found

Variant links:

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]

CHMP6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
CHMP6	NM_024591.5 link	c.317T>C	p.Phe106Ser	missense_variant	Exon 4 of 8	ENST00000325167.9	NP_078867.2	Q96FZ7
CHMP6	XM_005257668.1 link	c.317T>C	p.Phe106Ser	missense_variant	Exon 4 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHMP6	ENST00000325167.9 link	c.317T>C	p.Phe106Ser	missense_variant	Exon 4 of 8	1	NM_024591.5	ENSP00000317468.5	Q96FZ7
CHMP6	ENST00000572778.5 link	c.254T>C	p.Phe85Ser	missense_variant	Exon 3 of 6	2		ENSP00000461098.1	I3L4A1
CHMP6	ENST00000571457.1 link	c.191T>C	p.Phe64Ser	missense_variant	Exon 3 of 7	3		ENSP00000461238.1	I3L4G8
CHMP6	ENST00000572525.5 link	c.59T>C	p.Phe20Ser	missense_variant	Exon 4 of 8	3		ENSP00000460389.1	I3L3E4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727182

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 23, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.86

DEOGEN2

Benign

0.15

T;T;.;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.49

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.86

D;T;T;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.58

.;N;.;.

PhyloP100

7.5

PrimateAI

Benign

0.32

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

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

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17-80995727-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over