rs1053517

Variant names:

• chr2-206122291-A-G
• rs1053517
• NM_005006.7:c.*1894T>C

Variant summary

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

The NM_005006.7(NDUFS1):​c.*1894T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.524 in 151,580 control chromosomes in the GnomAD database, including 22,388 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 0.52 (22387 hom., cov: 29)
  • Exomes 𝑓: 0.36 (1 hom.)
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 7 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

ENSG00000231955 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.729 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	NM_005006.7	MANE Select	c.*1894T>C		3_prime_UTR	Exon 19 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.*1894T>C		3_prime_UTR	Exon 19 of 19	NP_001186913.1
	NDUFS1	NM_001199981.2		c.*1894T>C		3_prime_UTR	Exon 18 of 18	NP_001186910.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	ENST00000233190.11	TSL:1 MANE Select	c.*1894T>C		3_prime_UTR	Exon 19 of 19	ENSP00000233190.5
	ENSG00000231955	ENST00000453039.1	TSL:3	n.1379A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79283 AN: 151448 Hom.: 22345 Cov.: 29

Gnomad AFR AF: 0.736

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.533

Gnomad ASJ AF: 0.531

Gnomad EAS AF: 0.280

Gnomad SAS AF: 0.335

Gnomad FIN AF: 0.519

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.428

Gnomad OTH AF: 0.531

GnomAD4 exome AF: 0.357 AC: 5 AN: 14 Hom.: 1 Cov.: 0 AF XY: 0.500 AC XY: 3 AN XY: 6

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.417 AC: 5 AN: 12

Other (OTH) AF: 0.00 AC: 0 AN: 2

GnomAD4 genome AF: 0.524 AC: 79378 AN: 151566 Hom.: 22387 Cov.: 29 AF XY: 0.522 AC XY: 38654 AN XY: 74006

African (AFR) AF: 0.736 AC: 30436 AN: 41332

American (AMR) AF: 0.534 AC: 8118 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.531 AC: 1839 AN: 3466

East Asian (EAS) AF: 0.280 AC: 1431 AN: 5116

South Asian (SAS) AF: 0.336 AC: 1606 AN: 4778

European-Finnish (FIN) AF: 0.519 AC: 5433 AN: 10474

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29012 AN: 67870

Other (OTH) AF: 0.526 AC: 1113 AN: 2114

Alfa AF: 0.461 Hom.: 27724

Bravo AF: 0.533

Asia WGS AF: 0.320 AC: 1115 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	1.0
DANN	Benign	0.73
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs1053517; hg19: chr2-206987015;