16-89645971-C-T

Variant names:

• chr16-89645971-C-T
• rs61747591
• NM_002768.5:c.*95G>A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001083314.4(CHMP1A):​c.666G>A​(p.Ala222Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00401 in 1,611,724 control chromosomes in the GnomAD database, including 216 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (109 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (107 hom.)
• Consequence: CHMP1A NM_001083314.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.66

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-89645971-C-T is Benign according to our data. Variant chr16-89645971-C-T is described in ClinVar as [Benign]. Clinvar id is 383224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.66 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHMP1A	NM_002768.5	c.*95G>A		3_prime_UTR_variant	Exon 7 of 7	ENST00000397901.8	NP_002759.2
CHMP1A	NM_001083314.4	c.666G>A	p.Ala222Ala	synonymous_variant	Exon 6 of 6		NP_001076783.1
CHMP1A	XM_047434195.1	c.*95G>A		3_prime_UTR_variant	Exon 7 of 7		XP_047290151.1
CHMP1A	NR_046418.3	n.974G>A		non_coding_transcript_exon_variant	Exon 7 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHMP1A	ENST00000397901	c.*95G>A		3_prime_UTR_variant	Exon 7 of 7	1	NM_002768.5	ENSP00000380998.3

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3307 AN: 152202 Hom.: 110 Cov.: 33

Gnomad AFR AF: 0.0753

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00935

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00521 AC: 1271 AN: 244026 Hom.: 45 AF XY: 0.00390 AC XY: 520 AN XY: 133242

Gnomad AFR exome AF: 0.0753

Gnomad AMR exome AF: 0.00366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000154

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00216 AC: 3157 AN: 1459404 Hom.: 107 Cov.: 31 AF XY: 0.00190 AC XY: 1380 AN XY: 725970

Gnomad4 AFR exome AF: 0.0765

Gnomad4 AMR exome AF: 0.00384

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000314

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000783

Gnomad4 OTH exome AF: 0.00490

GnomAD4 genome AF: 0.0217 AC: 3310 AN: 152320 Hom.: 109 Cov.: 33 AF XY: 0.0211 AC XY: 1573 AN XY: 74468

Gnomad4 AFR AF: 0.0752

Gnomad4 AMR AF: 0.00934

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0113 Hom.: 28

Bravo AF: 0.0246

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Mar 11, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

CHMP1A-related disorder Benign:1

Mar 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.77
DANN	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs61747591; hg19: chr16-89712379;