19-17301211-C-A

Variant names:

• chr19-17301211-C-A
• rs762089945
• NM_024527.5:c.406G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024527.5(ABHD8):​c.406G>T​(p.Ala136Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 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. A136T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ABHD8 NM_024527.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.80
• Publications: 0 publications found

Genes affected

ABHD8 (HGNC:23759): (abhydrolase domain containing 8) This gene is upstream of, and in a head-to-head orientation with the gene for the mitochondrial ribosomal protein L34. The predicted protein contains alpha/beta hydrolase fold and secretory lipase domains. [provided by RefSeq, Jul 2008]

MRPL34 (HGNC:14488): (mitochondrial ribosomal protein L34) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 39S subunit protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061897784).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024527.5. 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
	ABHD8	NM_024527.5	MANE Select	c.406G>T	p.Ala136Ser	missense	Exon 2 of 5	NP_078803.4
	MRPL34	NM_001400072.1		c.-62-4620C>A		intron	N/A	NP_001387001.1	Q9BQ48
	MRPL34	NM_001400073.1		c.-63+2834C>A		intron	N/A	NP_001387002.1	Q9BQ48

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD8	ENST00000247706.4	TSL:1 MANE Select	c.406G>T	p.Ala136Ser	missense	Exon 2 of 5	ENSP00000247706.2	Q96I13
	ABHD8	ENST00000951444.1		c.406G>T	p.Ala136Ser	missense	Exon 2 of 5	ENSP00000621503.1
	ABHD8	ENST00000927605.1		c.406G>T	p.Ala136Ser	missense	Exon 2 of 4	ENSP00000597664.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.067
DANN	Benign	0.66
DEOGEN2	Benign	0.0065	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.086	N
LIST_S2	Benign	0.39	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		-2.8
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.17	N
REVEL	Benign	0.012
Sift	Benign	0.69	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.33		Gain of phosphorylation at A136 (P = 9e-04)
MVP		0.15
MPC		0.68
ClinPred		0.029	T
GERP RS		0.58
Varity_R		0.036
gMVP		0.48
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs762089945; hg19: chr19-17412020;