rs6435326

Variant names:

• chr2-206137835-A-T
• rs6435326
• NM_005006.7:c.1392+650T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005006.7(NDUFS1):​c.1392+650T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.535 in 152,106 control chromosomes in the GnomAD database, including 22,379 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (22379 hom., cov: 33)
• Consequence: NDUFS1 NM_005006.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.71
• Publications: 11 publications found

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]

NDUFS1 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial complex I deficiency, nuclear type 5

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.644 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005006.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	NM_005006.7	MANE Select	c.1392+650T>A		intron	N/A	NP_004997.4
	NDUFS1	NM_001199984.2		c.1434+650T>A		intron	N/A	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.1284+650T>A		intron	N/A	NP_001186910.1	P28331-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	ENST00000233190.11	TSL:1 MANE Select	c.1392+650T>A		intron	N/A	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903706.1		c.1392+650T>A		intron	N/A	ENSP00000573765.1
	NDUFS1	ENST00000449699.5	TSL:2	c.1392+650T>A		intron	N/A	ENSP00000399912.1	P28331-1

Frequencies

GnomAD3 genomes AF: 0.534 AC: 81229 AN: 151988 Hom.: 22347 Cov.: 33

Gnomad AFR AF: 0.651

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.584

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.372

Gnomad FIN AF: 0.564

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.485

Gnomad OTH AF: 0.553

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.535 AC: 81310 AN: 152106 Hom.: 22379 Cov.: 33 AF XY: 0.533 AC XY: 39600 AN XY: 74360

African (AFR) AF: 0.651 AC: 27001 AN: 41492

American (AMR) AF: 0.552 AC: 8436 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.584 AC: 2028 AN: 3470

East Asian (EAS) AF: 0.281 AC: 1455 AN: 5174

South Asian (SAS) AF: 0.373 AC: 1801 AN: 4828

European-Finnish (FIN) AF: 0.564 AC: 5952 AN: 10556

Middle Eastern (MID) AF: 0.582 AC: 171 AN: 294

European-Non Finnish (NFE) AF: 0.485 AC: 32992 AN: 68000

Other (OTH) AF: 0.547 AC: 1156 AN: 2112

Alfa AF: 0.517 Hom.: 2596

Bravo AF: 0.537

Asia WGS AF: 0.331 AC: 1152 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.7
DANN	Benign	0.67
PhyloP100		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6435326; hg19: chr2-207002559;