19-1383928-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024407.5(NDUFS7):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000028 in 1,428,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: NDUFS7 NM_024407.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.26

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1383928-T-C is Pathogenic according to our data. Variant chr19-1383928-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 214831.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS7	NM_024407.5	c.2T>C	p.Met1?	start_lost	1/8	ENST00000233627.14
NDUFS7	NM_001363602.2	c.2T>C	p.Met1?	start_lost	1/8
NDUFS7	XM_017026768.3	c.2T>C	p.Met1?	start_lost	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS7	ENST00000233627.14	c.2T>C	p.Met1?	start_lost	1/8	1	NM_024407.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1428548 Hom.: 0 Cov.: 32 AF XY: 0.00000424 AC XY: 3 AN XY: 707820

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: 0.00000365

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 30, 2013

p.Met1? (ATG>ACG): c.2 T>C in exon 1 of the NDUFS7 gene (NM_024407.4). The c.2 T>C mutation in the NDUFS7 gene alters the initiator Methionine codon and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. Although this mutation has not been reported previously to our knowledge, it is expected to be pathogenic. The variant is found in LSME-MITOP panel(s)." -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Uncertain	23
Dann	Benign	0.96
Eigen	Benign	-0.070
Eigen_PC	Benign	0.030
FATHMM_MKL	Benign	0.13	N
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-0.57	N;N;.;N;N;.;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D;D;.;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.12, 0.37	.;B;.;B;.;.;.
Vest4		0.77
MutPred		0.97		Gain of phosphorylation at M1 (P = 0.0396);Gain of phosphorylation at M1 (P = 0.0396);Gain of phosphorylation at M1 (P = 0.0396);Gain of phosphorylation at M1 (P = 0.0396);Gain of phosphorylation at M1 (P = 0.0396);Gain of phosphorylation at M1 (P = 0.0396);Gain of phosphorylation at M1 (P = 0.0396);
MVP		0.95
ClinPred		0.96	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.82
gMVP		0.40

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: rs863224113; hg19: chr19-1383927; COSMIC: COSV99282803; COSMIC: COSV99282803;