NM_005006.7:c.*158T>C

Variant names:

• chr2-206124027-A-G
• rs3770989
• NM_005006.7:c.*158T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005006.7(NDUFS1):​c.*158T>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 0.0307 in 617,484 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (86 hom., cov: 33)
  • Exomes 𝑓: 0.032 (289 hom.)
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.03
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-206124027-A-G is Benign according to our data. Variant chr2-206124027-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0261 (3975/152326) while in subpopulation SAS AF = 0.0431 (208/4826). AF 95% confidence interval is 0.0383. There are 86 homozygotes in GnomAd4. There are 1986 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 86 AR gene

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.*158T>C		3_prime_UTR	Exon 19 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.*158T>C		3_prime_UTR	Exon 19 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.*158T>C		3_prime_UTR	Exon 18 of 18	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.*158T>C		3_prime_UTR	Exon 19 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903706.1		c.*158T>C		3_prime_UTR	Exon 19 of 19	ENSP00000573765.1
	NDUFS1	ENST00000903708.1		c.*158T>C		3_prime_UTR	Exon 20 of 20	ENSP00000573767.1

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3968 AN: 152208 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.00651

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.0342

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0322 AC: 14974 AN: 465158 Hom.: 289 Cov.: 5 AF XY: 0.0330 AC XY: 8143 AN XY: 246396

African (AFR) AF: 0.00648 AC: 82 AN: 12650

American (AMR) AF: 0.0175 AC: 323 AN: 18494

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 441 AN: 14340

East Asian (EAS) AF: 0.0312 AC: 963 AN: 30862

South Asian (SAS) AF: 0.0436 AC: 1872 AN: 42946

European-Finnish (FIN) AF: 0.0249 AC: 832 AN: 33456

Middle Eastern (MID) AF: 0.0211 AC: 55 AN: 2612

European-Non Finnish (NFE) AF: 0.0339 AC: 9612 AN: 283376

Other (OTH) AF: 0.0301 AC: 794 AN: 26422

GnomAD4 genome AF: 0.0261 AC: 3975 AN: 152326 Hom.: 86 Cov.: 33 AF XY: 0.0267 AC XY: 1986 AN XY: 74486

African (AFR) AF: 0.00676 AC: 281 AN: 41586

American (AMR) AF: 0.0218 AC: 333 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.0341 AC: 177 AN: 5190

South Asian (SAS) AF: 0.0431 AC: 208 AN: 4826

European-Finnish (FIN) AF: 0.0284 AC: 301 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0345 AC: 2349 AN: 68032

Other (OTH) AF: 0.0218 AC: 46 AN: 2114

Alfa AF: 0.0310 Hom.: 10

Bravo AF: 0.0249

Asia WGS AF: 0.0420 AC: 147 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.87
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs3770989; hg19: chr2-206988751;