chr2-206124091-A-AT

Position:

• chr2-206124091-A-AT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The ENST00000233190.11(NDUFS1):​c.*93_*94insA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00202 in 798,554 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (3 hom.)
• Consequence: NDUFS1 ENST00000233190.11 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.29

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00271 (410/151496) while in subpopulation AFR AF= 0.00689 (285/41344). AF 95% confidence interval is 0.00624. There are 0 homozygotes in gnomad4. There are 194 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS1	NM_005006.7	c.*93_*94insA		3_prime_UTR_variant	19/19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11	c.*93_*94insA		3_prime_UTR_variant	19/19	1	NM_005006.7	ENSP00000233190	P1

Frequencies

GnomAD3 genomes AF: 0.00270 AC: 409 AN: 151380 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00689

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00119

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.000287

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00136

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.00186 AC: 1202 AN: 647058 Hom.: 3 Cov.: 9 AF XY: 0.00183 AC XY: 631 AN XY: 344510

Gnomad4 AFR exome AF: 0.00721

Gnomad4 AMR exome AF: 0.00132

Gnomad4 ASJ exome AF: 0.000369

Gnomad4 EAS exome AF: 0.000249

Gnomad4 SAS exome AF: 0.00170

Gnomad4 FIN exome AF: 0.000920

Gnomad4 NFE exome AF: 0.00206

Gnomad4 OTH exome AF: 0.00141

GnomAD4 genome AF: 0.00271 AC: 410 AN: 151496 Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 194 AN XY: 74030

Gnomad4 AFR AF: 0.00689

Gnomad4 AMR AF: 0.00119

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.000287

Gnomad4 NFE AF: 0.00136

Gnomad4 OTH AF: 0.00192

Bravo AF: 0.00288

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Mitochondrial complex I deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Leigh syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

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: rs200446477; hg19: chr2-206988815;