chr1-161199375-G-T

Position:

• chr1-161199375-G-T

Variant summary

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

The ENST00000367993.7(NDUFS2):​c.-388G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,320 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1445 hom., cov: 32)
  • Exomes 𝑓: 0.18 (0 hom.)
• Consequence: NDUFS2 ENST00000367993.7 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0180

Genes affected

NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-161199375-G-T is Benign according to our data. Variant chr1-161199375-G-T is described in ClinVar as [Benign]. Clinvar id is 293262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS2	NM_001377301.1	c.-388G>T		5_prime_UTR_variant	1/14
NDUFS2	NM_004550.5	c.-388G>T		5_prime_UTR_variant	1/15
NDUFS2	NM_001377298.1	c.-240+1888G>T		intron_variant
NDUFS2	NM_001377300.1	c.-240+1888G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS2	ENST00000367993.7	c.-388G>T		5_prime_UTR_variant	1/15	1		P1
NDUFS2	ENST00000679176.1	c.-388G>T		5_prime_UTR_variant	1/14
NDUFS2	ENST00000676600.1	c.-77+1888G>T		intron_variant				P1

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18650 AN: 152136 Hom.: 1449 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.0992

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.182 AC: 12 AN: 66 Hom.: 0 Cov.: 0 AF XY: 0.196 AC XY: 9 AN XY: 46

Gnomad4 ASJ exome AF: 0.500

Gnomad4 EAS exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.208

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.122 AC: 18637 AN: 152254 Hom.: 1445 Cov.: 32 AF XY: 0.123 AC XY: 9178 AN XY: 74454

Gnomad4 AFR AF: 0.0479

Gnomad4 AMR AF: 0.203

Gnomad4 ASJ AF: 0.175

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.0978

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.136

Gnomad4 OTH AF: 0.128

Alfa AF: 0.122 Hom.: 525

Bravo AF: 0.129

Asia WGS AF: 0.203 AC: 704 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Mitochondrial complex 1 deficiency, nuclear type 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.79
CADD	Benign	4.3
DANN	Benign	0.82

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: rs3813623; hg19: chr1-161169165;