17-80994651-G-A

Variant names:

• chr17-80994651-G-A
• rs370737009
• NM_024591.5:c.134G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_024591.5(CHMP6):​c.134G>A​(p.Arg45His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000107 in 1,584,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CHMP6 NM_024591.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.35

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.78

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.134G>A	p.Arg45His	missense_variant	Exon 2 of 8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.134G>A	p.Arg45His	missense_variant	Exon 2 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9	c.134G>A	p.Arg45His	missense_variant	Exon 2 of 8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572778.5	c.71G>A	p.Arg24His	missense_variant	Exon 1 of 6	2		ENSP00000461098.1
CHMP6	ENST00000571457.1	c.8G>A	p.Arg3His	missense_variant	Exon 1 of 7	3		ENSP00000461238.1
CHMP6	ENST00000572525.5	c.-125G>A		5_prime_UTR_variant	Exon 2 of 8	3		ENSP00000460389.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000681 AC: 13 AN: 190976 AF XY: 0.0000965

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000362

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000858

Gnomad OTH exome AF: 0.000413

GnomAD4 exome AF: 0.000106 AC: 152 AN: 1431774 Hom.: 0 Cov.: 31 AF XY: 0.000116 AC XY: 82 AN XY: 709360

African (AFR) AF: 0.0000606 AC: 2 AN: 33016

American (AMR) AF: 0.000153 AC: 6 AN: 39268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25444

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38478

South Asian (SAS) AF: 0.000135 AC: 11 AN: 81628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49544

Middle Eastern (MID) AF: 0.00140 AC: 8 AN: 5718

European-Non Finnish (NFE) AF: 0.000101 AC: 111 AN: 1099318

Other (OTH) AF: 0.000219 AC: 13 AN: 59360

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74470

African (AFR) AF: 0.00 AC: 0 AN: 41562

American (AMR) AF: 0.000196 AC: 3 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000141 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000235 AC: 2

ExAC AF: 0.000144 AC: 17

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.134G>A (p.R45H) alteration is located in exon 2 (coding exon 2) of the CHMP6 gene. This alteration results from a G to A substitution at nucleotide position 134, causing the arginine (R) at amino acid position 45 to be replaced by a histidine (H). 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	0.17
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.45	T;.;.
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.1	M;.;.
PhyloP100		7.3
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.6	D;.;.
REVEL	Uncertain	0.59
Sift	Benign	0.075	T;.;.
Sift4G	Benign	0.11	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.62
MVP		0.51
MPC		0.37
ClinPred		0.83	D
GERP RS		4.4
PromoterAI		0.0092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.42
Mutation Taster		=46/54	disease causing

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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Other links and lift over

dbSNP: rs370737009; hg19: chr17-78968451;