chr16-89651623-C-T

Variant names:

• chr16-89651623-C-T
• rs187184327
• NM_002768.5:c.51G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_001083314.4(CHMP1A):​c.31G>A​(p.Ala11Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000678 in 1,613,756 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 6/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A11P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00063 (1 hom.)
• Consequence: CHMP1A NM_001083314.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.116
• Publications: 4 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.184).
• BP6: Variant 16-89651623-C-T is Benign according to our data. Variant chr16-89651623-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128732.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00114 (174/152354) while in subpopulation AMR AF = 0.00529 (81/15304). AF 95% confidence interval is 0.00436. There are 0 homozygotes in GnomAd4. There are 72 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001083314.4. 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
	CHMP1A	NM_002768.5	MANE Select	c.51G>A	p.Lys17Lys	synonymous	Exon 3 of 7	NP_002759.2	Q9HD42-1
	CHMP1A	NM_001083314.4		c.31G>A	p.Ala11Thr	missense	Exon 2 of 6	NP_001076783.1
	CHMP1A	NR_046418.3		n.171G>A		non_coding_transcript_exon	Exon 3 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP1A	ENST00000397901.8	TSL:1 MANE Select	c.51G>A	p.Lys17Lys	synonymous	Exon 3 of 7	ENSP00000380998.3	Q9HD42-1
	CHMP1A	ENST00000675536.1		c.51G>A	p.Lys17Lys	synonymous	Exon 3 of 7	ENSP00000501759.1	A0A6Q8PFF8
	CHMP1A	ENST00000535997.7	TSL:2	c.51G>A	p.Lys17Lys	synonymous	Exon 3 of 7	ENSP00000442120.3	F5H875

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152236 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.000717 AC: 178 AN: 248390 AF XY: 0.000659

Gnomad AFR exome AF: 0.000130

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000605

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.000630 AC: 920 AN: 1461402 Hom.: 1 Cov.: 31 AF XY: 0.000597 AC XY: 434 AN XY: 726962

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26130

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53202

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000631 AC: 701 AN: 1111808

Other (OTH) AF: 0.000812 AC: 49 AN: 60354

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152354 Hom.: 0 Cov.: 33 AF XY: 0.000966 AC XY: 72 AN XY: 74504

African (AFR) AF: 0.000216 AC: 9 AN: 41582

American (AMR) AF: 0.00529 AC: 81 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68038

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.000876 Hom.: 1

Bravo AF: 0.00170

EpiCase AF: 0.000655

EpiControl AF: 0.000711

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	CHMP1A-related disorder (1)
-	-	1	not specified (1)
-	1	-	Pontocerebellar hypoplasia type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	6.6
DANN	Benign	0.86
PhyloP100		0.12
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs187184327; hg19: chr16-89718031;