19-1391060-G-T

Position:

• chr19-1391060-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024407.5(NDUFS7):​c.408+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,612,552 control chromosomes in the GnomAD database, including 3,963 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (545 hom., cov: 33)
  • Exomes 𝑓: 0.042 (3418 hom.)
• Consequence: NDUFS7 NM_024407.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.03

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]

NDUFS7 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-1391060-G-T is Benign according to our data. Variant chr19-1391060-G-T is described in ClinVar as [Benign]. Clinvar id is 138498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS7	NM_024407.5	c.408+10G>T		intron_variant		ENST00000233627.14	NP_077718.3
NDUFS7	NM_001363602.2	c.408+10G>T		intron_variant			NP_001350531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000233627.14	c.408+10G>T		intron_variant		1	NM_024407.5	ENSP00000233627.9

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9119 AN: 151920 Hom.: 540 Cov.: 33

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.0186

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0303

Gnomad EAS AF: 0.249

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0242

Gnomad OTH AF: 0.0479

GnomAD3 exomes AF: 0.0784 AC: 19390 AN: 247420 Hom.: 1533 AF XY: 0.0747 AC XY: 10041 AN XY: 134462

Gnomad AFR exome AF: 0.0657

Gnomad AMR exome AF: 0.178

Gnomad ASJ exome AF: 0.0274

Gnomad EAS exome AF: 0.250

Gnomad SAS exome AF: 0.134

Gnomad FIN exome AF: 0.0118

Gnomad NFE exome AF: 0.0247

Gnomad OTH exome AF: 0.0526

GnomAD4 exome AF: 0.0421 AC: 61501 AN: 1460514 Hom.: 3418 Cov.: 33 AF XY: 0.0436 AC XY: 31656 AN XY: 726598

Gnomad4 AFR exome AF: 0.0666

Gnomad4 AMR exome AF: 0.174

Gnomad4 ASJ exome AF: 0.0267

Gnomad4 EAS exome AF: 0.246

Gnomad4 SAS exome AF: 0.129

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.0234

Gnomad4 OTH exome AF: 0.0509

GnomAD4 genome AF: 0.0602 AC: 9159 AN: 152038 Hom.: 545 Cov.: 33 AF XY: 0.0643 AC XY: 4778 AN XY: 74346

Gnomad4 AFR AF: 0.0698

Gnomad4 AMR AF: 0.151

Gnomad4 ASJ AF: 0.0303

Gnomad4 EAS AF: 0.250

Gnomad4 SAS AF: 0.140

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0242

Gnomad4 OTH AF: 0.0526

Alfa AF: 0.0291 Hom.: 167

Bravo AF: 0.0674

Asia WGS AF: 0.210 AC: 729 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 24, 2016	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 26, 2012

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.18
DANN	Benign	0.75

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: rs2074896; hg19: chr19-1391059; COSMIC: COSV52038641; COSMIC: COSV52038641;