16-89649393-G-C

Variant names:

• chr16-89649393-G-C
• rs114931496
• NM_002768.5:c.210C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002768.5(CHMP1A):​c.210C>G​(p.Asp70Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D70D) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CHMP1A NM_002768.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 0 publications found

Genes affected

CHMP1A (HGNC:8740): (charged multivesicular body protein 1A) This gene encodes a member of the CHMP/Chmp family of proteins which are involved in multivesicular body sorting of proteins to the interiors of lysosomes. The initial prediction of the protein sequence encoded by this gene suggested that the encoded protein was a metallopeptidase. The nomenclature has been updated recently to reflect the correct biological function of this encoded protein. Several transcripts encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

CHMP1A Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 8

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.901

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002768.5. 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
	CHMP1A	NM_002768.5	MANE Select	c.210C>G	p.Asp70Glu	missense	Exon 4 of 7	NP_002759.2	Q9HD42-1
	CHMP1A	NM_001083314.4		c.190C>G	p.Arg64Gly	missense	Exon 3 of 6	NP_001076783.1
	CHMP1A	NR_046418.3		n.330C>G		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP1A	ENST00000397901.8	TSL:1 MANE Select	c.210C>G	p.Asp70Glu	missense	Exon 4 of 7	ENSP00000380998.3	Q9HD42-1
	CHMP1A	ENST00000675536.1		c.265C>G	p.Arg89Gly	missense	Exon 4 of 7	ENSP00000501759.1	A0A6Q8PFF8
	CHMP1A	ENST00000535997.7	TSL:2	c.210C>G	p.Asp70Glu	missense	Exon 4 of 7	ENSP00000442120.3	F5H875

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461364 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726940

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111830

Other (OTH) AF: 0.00 AC: 0 AN: 60370

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	1.5
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.099	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		-1.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.71		Loss of ubiquitination at K75 (P = 0.1322)
MVP		0.65
MPC		1.1
ClinPred		0.98	D
GERP RS		-5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.93

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: rs114931496; hg19: chr16-89715801;