8-81758536-G-A

Variant names:

• chr8-81758536-G-A
• rs35094336
• NM_152284.4:c.694G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152284.4(CHMP4C):​c.694G>A​(p.Ala232Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0633 in 1,608,078 control chromosomes in the GnomAD database, including 3,551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (224 hom., cov: 32)
  • Exomes 𝑓: 0.065 (3327 hom.)
• Consequence: CHMP4C NM_152284.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.15
• Publications: 26 publications found

Genes affected

CHMP4C (HGNC:30599): (charged multivesicular body protein 4C) CHMP4C belongs to the chromatin-modifying protein/charged multivesicular body protein (CHMP) family. These proteins are components of ESCRT-III (endosomal sorting complex required for transport III), a complex involved in degradation of surface receptor proteins and formation of endocytic multivesicular bodies (MVBs). Some CHMPs have both nuclear and cytoplasmic/vesicular distributions, and one such CHMP, CHMP1A (MIM 164010), is required for both MVB formation and regulation of cell cycle progression (Tsang et al., 2006 [PubMed 16730941]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019286573).
• BP6: Variant 8-81758536-G-A is Benign according to our data. Variant chr8-81758536-G-A is described in ClinVar as Benign. ClinVar VariationId is 1225623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0746 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152284.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP4C	NM_152284.4	MANE Select	c.694G>A	p.Ala232Thr	missense	Exon 5 of 5	NP_689497.1	Q96CF2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP4C	ENST00000297265.5	TSL:1 MANE Select	c.694G>A	p.Ala232Thr	missense	Exon 5 of 5	ENSP00000297265.4	Q96CF2

Frequencies

GnomAD3 genomes AF: 0.0506 AC: 7697 AN: 152088 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.0515

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.0866

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0815

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.117

Gnomad NFE AF: 0.0676

Gnomad OTH AF: 0.0516

GnomAD2 exomes AF: 0.0540 AC: 13565 AN: 250974 AF XY: 0.0567

Gnomad AFR exome AF: 0.0246

Gnomad AMR exome AF: 0.0286

Gnomad ASJ exome AF: 0.0793

Gnomad EAS exome AF: 0.000218

Gnomad FIN exome AF: 0.0438

Gnomad NFE exome AF: 0.0691

Gnomad OTH exome AF: 0.0589

GnomAD4 exome AF: 0.0646 AC: 94107 AN: 1455872 Hom.: 3327 Cov.: 28 AF XY: 0.0657 AC XY: 47624 AN XY: 724604

African (AFR) AF: 0.0281 AC: 938 AN: 33380

American (AMR) AF: 0.0313 AC: 1399 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0811 AC: 2116 AN: 26100

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39666

South Asian (SAS) AF: 0.0740 AC: 6374 AN: 86122

European-Finnish (FIN) AF: 0.0468 AC: 2497 AN: 53408

Middle Eastern (MID) AF: 0.104 AC: 593 AN: 5724

European-Non Finnish (NFE) AF: 0.0689 AC: 76273 AN: 1106618

Other (OTH) AF: 0.0649 AC: 3905 AN: 60192

GnomAD4 genome AF: 0.0506 AC: 7699 AN: 152206 Hom.: 224 Cov.: 32 AF XY: 0.0505 AC XY: 3758 AN XY: 74402

African (AFR) AF: 0.0256 AC: 1062 AN: 41534

American (AMR) AF: 0.0452 AC: 691 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0866 AC: 300 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0812 AC: 392 AN: 4828

European-Finnish (FIN) AF: 0.0441 AC: 467 AN: 10582

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0676 AC: 4594 AN: 67998

Other (OTH) AF: 0.0506 AC: 107 AN: 2114

Alfa AF: 0.0635 Hom.: 866

Bravo AF: 0.0474

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0703 AC: 271

ESP6500AA AF: 0.0300 AC: 132

ESP6500EA AF: 0.0666 AC: 573

ExAC AF: 0.0555 AC: 6740

Asia WGS AF: 0.0290 AC: 103 AN: 3478

EpiCase AF: 0.0689

EpiControl AF: 0.0731

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.0	N
PhyloP100		4.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.27
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.14
MPC		0.11
ClinPred		0.017	T
GERP RS		6.1
Varity_R		0.83
gMVP		0.55
Mutation Taster		=76/24	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs35094336; hg19: chr8-82670771; COSMIC: COSV51929166;