dbSNP rs114931496: CHMP1A:p.Asp70Asp (chr16-89649393-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4BP6BS1BS2

The NM_001083314.4(CHMP1A):c.190C>T(p.Arg64Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000864 in 1,613,678 control chromosomes in the GnomAD database, including 12 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. R64H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0040 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00053 ( 7 hom. )

Consequence

CHMP1A
NM_001083314.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -1.10

Publications

2 publications found

Variant links:

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

CHMP1A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.184).

BP6

Variant 16-89649393-G-A is Benign according to our data. Variant chr16-89649393-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210727.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00404 (615/152318) while in subpopulation AFR AF = 0.0138 (573/41552). AF 95% confidence interval is 0.0129. There are 5 homozygotes in GnomAd4. There are 283 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHMP1A	NM_002768.5	MANE Select	c.210C>T	p.Asp70Asp	synonymous	Exon 4 of 7	NP_002759.2	Q9HD42-1
CHMP1A	NM_001083314.4		c.190C>T	p.Arg64Cys	missense	Exon 3 of 6	NP_001076783.1
CHMP1A	NR_046418.3		n.330C>T		non_coding_transcript_exon	Exon 4 of 7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CHMP1A	ENST00000397901.8	TSL:1 MANE Select	c.210C>T	p.Asp70Asp	synonymous	Exon 4 of 7	ENSP00000380998.3	Q9HD42-1
CHMP1A	ENST00000675536.1		c.265C>T	p.Arg89Cys	missense	Exon 4 of 7	ENSP00000501759.1	A0A6Q8PFF8
CHMP1A	ENST00000535997.7	TSL:2	c.210C>T	p.Asp70Asp	synonymous	Exon 4 of 7	ENSP00000442120.3	F5H875

Frequencies

GnomAD3 genomes

AF:

0.00403

AC:

614

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0138

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00110

AC:

273

AN:

248896

AF XY:

0.000814

show subpopulations

Gnomad AFR exome

AF:

0.0147

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000532

Gnomad OTH exome

AF:

0.000661

GnomAD4 exome

AF:

0.000533

AC:

779

AN:

1461360

Hom.:

Cov.:

AF XY:

0.000483

AC XY:

351

AN XY:

726940

show subpopulations

African (AFR)

AF:

0.0170

AC:

568

AN:

33474

American (AMR)

AF:

0.000760

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000394

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000729

AC:

AN:

1111830

Other (OTH)

AF:

0.000977

AC:

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

135

180

225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00404

AC:

615

AN:

152318

Hom.:

Cov.:

AF XY:

0.00380

AC XY:

283

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0138

AC:

573

AN:

41552

American (AMR)

AF:

0.00163

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68032

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00505

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

CHMP1A-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.23

(source)

DANN

Benign

0.80

PhyloP100

-1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over