rs61730919

Variant names:

• chr16-89646688-G-A
• rs61730919
• NM_002768.5:c.408C>T

Your query was ambiguous. Multiple possible variants found:

• chr16-89646688-G-A
• chr16-89646688-G-T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS1

The NM_001083314.4(CHMP1A):​c.388C>T​(p.His130Tyr) variant causes a missense 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. 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).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00033 (0 hom.)
• Consequence: CHMP1A NM_001083314.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.838
• Publications: 2 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.117).
• 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 VariationId is 390042.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00044 (67/152188) while in subpopulation NFE AF = 0.000661 (45/68034). AF 95% confidence interval is 0.000508. There are 0 homozygotes in GnomAd4. There are 35 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.408C>T	p.Ala136Ala	synonymous	Exon 6 of 7	NP_002759.2	Q9HD42-1
	CHMP1A	NM_001083314.4		c.388C>T	p.His130Tyr	missense	Exon 5 of 6	NP_001076783.1
	CHMP1A	NR_046418.3		n.696C>T		non_coding_transcript_exon	Exon 6 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHMP1A	ENST00000397901.8	TSL:1 MANE Select	c.408C>T	p.Ala136Ala	synonymous	Exon 6 of 7	ENSP00000380998.3	Q9HD42-1
	CHMP1A	ENST00000547687.2	TSL:1	n.1156C>T		non_coding_transcript_exon	Exon 1 of 2
	CHMP1A	ENST00000675536.1		c.463C>T	p.His155Tyr	missense	Exon 6 of 7	ENSP00000501759.1	A0A6Q8PFF8

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

GnomAD2 exomes AF: 0.000320 AC: 77 AN: 240492 AF XY: 0.000290

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 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

African (AFR) AF: 0.000239 AC: 8 AN: 33446

American (AMR) AF: 0.000203 AC: 9 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 85446

European-Finnish (FIN) AF: 0.000211 AC: 11 AN: 52250

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000387 AC: 430 AN: 1110908

Other (OTH) AF: 0.000183 AC: 11 AN: 60252

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

African (AFR) AF: 0.000314 AC: 13 AN: 41438

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000661 AC: 45 AN: 68034

Other (OTH) AF: 0.00143 AC: 3 AN: 2092

Alfa AF: 0.000548 Hom.: 0

Bravo AF: 0.000385

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs61730919; hg19: chr16-89713096;