4-139275315-C-T

Variant names:

• chr4-139275315-C-T
• rs376742509
• NM_032623.4:c.160G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_032623.4(MGARP):​c.160G>A​(p.Val54Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,613,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: MGARP NM_032623.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17
• Publications: 2 publications found

Genes affected

MGARP (HGNC:29969): (mitochondria localized glutamic acid rich protein) Predicted to be involved in several processes, including axonal transport; cellular response to hormone stimulus; and protein targeting to mitochondrion. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

NDUFC1 (HGNC:7705): (NADH:ubiquinone oxidoreductase subunit C1) The encoded protein is a subunit of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, May 2010]

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.38550344).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032623.4. 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
	MGARP	NM_032623.4	MANE Select	c.160G>A	p.Val54Ile	missense	Exon 2 of 4	NP_116012.2	Q8TDB4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MGARP	ENST00000398955.2	TSL:1 MANE Select	c.160G>A	p.Val54Ile	missense	Exon 2 of 4	ENSP00000381928.1	Q8TDB4
	MGARP	ENST00000962439.1		c.160G>A	p.Val54Ile	missense	Exon 2 of 4	ENSP00000632498.1
	NDUFC1	ENST00000503997.5	TSL:3	n.*98G>A		non_coding_transcript_exon	Exon 4 of 6	ENSP00000425882.1	O43677

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000108 AC: 27 AN: 249344 AF XY: 0.000133

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.000278

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000109 AC: 160 AN: 1461578 Hom.: 0 Cov.: 30 AF XY: 0.000122 AC XY: 89 AN XY: 727090

African (AFR) AF: 0.0000598 AC: 2 AN: 33468

American (AMR) AF: 0.0000224 AC: 1 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.000421 AC: 11 AN: 26130

East Asian (EAS) AF: 0.000580 AC: 23 AN: 39676

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.0000953 AC: 106 AN: 1111816

Other (OTH) AF: 0.000182 AC: 11 AN: 60378

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.0000942 AC XY: 7 AN XY: 74318

African (AFR) AF: 0.0000241 AC: 1 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000576 AC: 3 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000196 Hom.: 0

Bravo AF: 0.000106

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000108 AC: 13

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.047	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.91	N
REVEL	Benign	0.15
Sift	Uncertain	0.013	D
Sift4G	Benign	0.069	T
Polyphen		1.0	D
Vest4		0.53
MutPred		0.27		Loss of catalytic residue at V54 (P = 0.0015)
MVP		0.53
MPC		0.50
ClinPred		0.23	T
GERP RS		5.9
Varity_R		0.16
gMVP		0.34
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs376742509; hg19: chr4-140196469; COSMIC: COSV67449383;