Genetic Variant DMAC1:p.Ala24Gly (chr9-7799664-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033428.3(DMAC1):c.71C>G(p.Ala24Gly) 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 1,455,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DMAC1
NM_033428.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

Variant links:

Genes affected

DMAC1 (HGNC:30536): (distal membrane arm assembly component 1) Involved in mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Colocalizes with mitochondrial respiratory chain complex I. [provided by Alliance of Genome Resources, Apr 2022]

DMAC1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17523062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DMAC1	NM_033428.3 link	c.71C>G	p.Ala24Gly	missense_variant	Exon 1 of 2	ENST00000358227.5	NP_219500.1
DMAC1	NM_001318059.2 link	c.71C>G	p.Ala24Gly	missense_variant	Exon 1 of 2		NP_001304988.1
DMAC1	NM_001318058.2 link	c.71C>G	p.Ala24Gly	missense_variant	Exon 1 of 2		NP_001304987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
DMAC1	ENST00000358227.5 link	c.71C>G	p.Ala24Gly	missense_variant	Exon 1 of 2	1	NM_033428.3	ENSP00000350961.4	Q96GE9-2
DMAC1	ENST00000469050.1 link	n.165-1027C>G		intron_variant	Intron 2 of 2	3
DMAC1	ENST00000484082.1 link	n.108+377C>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243320

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132216

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000908

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1455936

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

724012

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71C>G (p.A24G) alteration is located in exon 1 (coding exon 1) of the TMEM261 gene. This alteration results from a C to G substitution at nucleotide position 71, causing the alanine (A) at amino acid position 24 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.070

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.38

M_CAP

Benign

0.037

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.88

PROVEAN

Benign

-2.1

REVEL

Benign

0.14

Sift

Benign

0.067

Sift4G

Uncertain

0.035

Polyphen

0.97

Vest4

0.25

MutPred

0.049

Loss of glycosylation at P23 (P = 0.1119);

MVP

0.51

MPC

0.25

ClinPred

0.49

GERP RS

4.8

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over