9-7799640-G-T

Position:

• chr9-7799640-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033428.3(DMAC1):​c.95C>A​(p.Pro32His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DMAC1 NM_033428.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.47

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29654986).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DMAC1	NM_033428.3	c.95C>A	p.Pro32His	missense_variant	1/2	ENST00000358227.5	NP_219500.1
DMAC1	NM_001318059.2	c.95C>A	p.Pro32His	missense_variant	1/2		NP_001304988.1
DMAC1	NM_001318058.2	c.95C>A	p.Pro32His	missense_variant	1/2		NP_001304987.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DMAC1	ENST00000358227.5	c.95C>A	p.Pro32His	missense_variant	1/2	1	NM_033428.3	ENSP00000350961.4
DMAC1	ENST00000469050.1	n.165-1003C>A		intron_variant		3
DMAC1	ENST00000484082.1	n.108+401C>A		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 64

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2024

The c.95C>A (p.P32H) alteration is located in exon 1 (coding exon 1) of the TMEM261 gene. This alteration results from a C to A substitution at nucleotide position 95, causing the proline (P) at amino acid position 32 to be replaced by a histidine (H). 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	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	23
DANN	Uncertain	1.0
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.81	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Benign	0.15
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.17
MutPred		0.19		Loss of glycosylation at P32 (P = 0.0135);
MVP		0.48
MPC		0.70
ClinPred		0.93	D
GERP RS		4.4
gMVP		0.51

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

Other links and lift over

dbSNP: rs745628156; hg19: chr9-7799640; COSMIC: COSV64065982;