2-206123728-A-T

Variant summary

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

The NM_005006.7(NDUFS1):c.*457T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0623 in 155,194 control chromosomes in the GnomAD database, including 393 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.062 (383 hom., cov: 32)
  • Exomes 𝑓: 0.058 (10 hom.)
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.43

Genes affected

NDUFS1 (HGNC:7707): (NADH:ubiquinone oxidoreductase core subunit S1) The protein encoded by this gene belongs to the complex I 75 kDa subunit family. Mammalian complex I is composed of 45 different subunits. It locates at the mitochondrial inner membrane. This protein has NADH dehydrogenase activity and oxidoreductase activity. It transfers electrons from NADH to the respiratory chain. The immediate electron acceptor for the enzyme is believed to be ubiquinone. This protein is the largest subunit of complex I and it is a component of the iron-sulfur (IP) fragment of the enzyme. It may form part of the active site crevice where NADH is oxidized. Mutations in this gene are associated with complex I deficiency. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-206123728-A-T is Benign according to our data. Variant chr2-206123728-A-T is described in ClinVar as [Benign]. Clinvar id is 333771.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.165 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NDUFS1	NM_005006.7	c.*457T>A		3_prime_UTR_variant	19/19	ENST00000233190.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NDUFS1	ENST00000233190.11	c.*457T>A		3_prime_UTR_variant	19/19	1	NM_005006.7	P1

Frequencies

GnomAD3 genomes AF: 0.0625 AC: 9497 AN: 152050 Hom.: 383 Cov.: 32

Gnomad AFR AF: 0.0247

Gnomad AMI AF: 0.159

Gnomad AMR AF: 0.0607

Gnomad ASJ AF: 0.0956

Gnomad EAS AF: 0.174

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0752

Gnomad OTH AF: 0.0688

GnomAD4 exome AF: 0.0578 AC: 175 AN: 3026 Hom.: 10 Cov.: 0 AF XY: 0.0583 AC XY: 99 AN XY: 1698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0434

Gnomad4 ASJ exome AF: 0.0556

Gnomad4 EAS exome AF: 0.151

Gnomad4 SAS exome AF: 0.0861

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0574

Gnomad4 OTH exome AF: 0.0175

GnomAD4 genome AF: 0.0624 AC: 9491 AN: 152168 Hom.: 383 Cov.: 32 AF XY: 0.0624 AC XY: 4646 AN XY: 74414

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.0605

Gnomad4 ASJ AF: 0.0956

Gnomad4 EAS AF: 0.174

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0752

Gnomad4 OTH AF: 0.0686

Alfa AF: 0.0247 Hom.: 10

Bravo AF: 0.0621

Asia WGS AF: 0.144 AC: 500 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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. -

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 13, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	2.1
Dann	Benign	0.65

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: rs4147728; hg19: chr2-206988452;