16-89646688-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001083314.4(CHMP1A):​c.388C>A​(p.His130Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,048 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H130Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHMP1A NM_001083314.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.838
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (REVEL=0.143).

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>A	p.Ala136Ala	synonymous	Exon 6 of 7	NP_002759.2	Q9HD42-1
	CHMP1A	NM_001083314.4		c.388C>A	p.His130Asn	missense	Exon 5 of 6	NP_001076783.1
	CHMP1A	NR_046418.3		n.696C>A		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>A	p.Ala136Ala	synonymous	Exon 6 of 7	ENSP00000380998.3	Q9HD42-1
	CHMP1A	ENST00000547687.2	TSL:1	n.1156C>A		non_coding_transcript_exon	Exon 1 of 2
	CHMP1A	ENST00000675536.1		c.463C>A	p.His155Asn	missense	Exon 6 of 7	ENSP00000501759.1	A0A6Q8PFF8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458048 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 724954

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.00 AC: 0 AN: 44338

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 52250

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

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110908

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61730919; hg19: chr16-89713096;