rs61730919

Positions:

• chr16-89646688-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_002768.5(CHMP1A):​c.408C>T​(p.Ala136=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000336 in 1,610,236 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CHMP1A NM_002768.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.838

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-89646688-G-A is Benign according to our data. Variant chr16-89646688-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 390042.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BP7: Synonymous conserved (PhyloP=0.838 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHMP1A	NM_002768.5	c.408C>T	p.Ala136=	synonymous_variant	6/7	ENST00000397901.8
CHMP1A	NM_001083314.4	c.388C>T	p.His130Tyr	missense_variant	5/6
CHMP1A	XM_047434195.1	c.216C>T	p.Ala72=	synonymous_variant	6/7
CHMP1A	NR_046418.3	n.696C>T		non_coding_transcript_exon_variant	6/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHMP1A	ENST00000397901.8	c.408C>T	p.Ala136=	synonymous_variant	6/7	1	NM_002768.5	P1

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152188 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000661

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000320 AC: 77 AN: 240492 Hom.: 0 AF XY: 0.000290 AC XY: 38 AN XY: 131174

Gnomad AFR exome AF: 0.000347

Gnomad AMR exome AF: 0.000147

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000241

Gnomad NFE exome AF: 0.000544

Gnomad OTH exome AF: 0.000171

GnomAD4 exome AF: 0.000325 AC: 474 AN: 1458048 Hom.: 0 Cov.: 33 AF XY: 0.000321 AC XY: 233 AN XY: 724954

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.000192

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000211

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.000183

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152188 Hom.: 0 Cov.: 33 AF XY: 0.000471 AC XY: 35 AN XY: 74336

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.000661

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000479 Hom.: 0

Bravo AF: 0.000385

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 01, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.388C>T (p.H130Y) alteration is located in exon 5 (coding exon 5) of the CHMP1A gene. This alteration results from a C to T substitution at nucleotide position 388, causing the histidine (H) at amino acid position 130 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 27, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs61730919; hg19: chr16-89713096;