17-80991953-G-T

Variant names:

• chr17-80991953-G-T
• rs757131739
• NM_024591.5:c.35G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_024591.5(CHMP6):​c.35G>T​(p.Arg12Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHMP6 NM_024591.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.86
• Publications: 0 publications found

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP6	NM_024591.5	c.35G>T	p.Arg12Leu	missense_variant	Exon 1 of 8	ENST00000325167.9	NP_078867.2
CHMP6	XM_005257668.1	c.35G>T	p.Arg12Leu	missense_variant	Exon 1 of 7		XP_005257725.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP6	ENST00000325167.9	c.35G>T	p.Arg12Leu	missense_variant	Exon 1 of 8	1	NM_024591.5	ENSP00000317468.5
CHMP6	ENST00000572525.5	c.-196+280G>T		intron_variant	Intron 1 of 7	3		ENSP00000460389.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 106754 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1315282 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 650046

African (AFR) AF: 0.00 AC: 0 AN: 26648

American (AMR) AF: 0.00 AC: 0 AN: 28844

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22112

East Asian (EAS) AF: 0.00 AC: 0 AN: 28014

South Asian (SAS) AF: 0.00 AC: 0 AN: 73344

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43840

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4546

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1035094

Other (OTH) AF: 0.00 AC: 0 AN: 52840

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.97	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		3.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.52		Gain of ubiquitination at K9 (P = 0.0408);
MVP		0.60
MPC		0.42
ClinPred		1.0	D
GERP RS		1.7
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.90
gMVP		0.34

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

Other links and lift over

dbSNP: rs757131739; hg19: chr17-78965753;