19-1391006-G-T

Position:

• chr19-1391006-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_024407.5(NDUFS7):​c.364G>T​(p.Val122Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V122M) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NDUFS7 NM_024407.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.43

Genes affected

NDUFS7 (HGNC:7714): (NADH:ubiquinone oxidoreductase core subunit S7) This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a chain NADH dehydrogenase [ubiquinone] iron-sulfur protein 7, mitochondrial (size 174) in uniprot entity NDUS7_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_024407.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1391006-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7681.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS7	NM_024407.5	c.364G>T	p.Val122Leu	missense_variant	5/8	ENST00000233627.14
NDUFS7	NM_001363602.2	c.364G>T	p.Val122Leu	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS7	ENST00000233627.14	c.364G>T	p.Val122Leu	missense_variant	5/8	1	NM_024407.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460992 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726836

Gnomad4 AFR exome AF: 0.0000299

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Benign	0.97
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.4	M;M;.;.;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.8	D;D;.;D;D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D;.;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D;D
Polyphen		1.0, 1.0	.;D;.;D;.;.;.
Vest4		0.78
MutPred		0.67		Loss of catalytic residue at V122 (P = 0.0219);Loss of catalytic residue at V122 (P = 0.0219);Loss of catalytic residue at V122 (P = 0.0219);Loss of catalytic residue at V122 (P = 0.0219);Loss of catalytic residue at V122 (P = 0.0219);Loss of catalytic residue at V122 (P = 0.0219);.;
MVP		0.97
MPC		1.4
ClinPred		0.96	D
GERP RS		4.6
Varity_R		0.89
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894705; hg19: chr19-1391005;