2-206138506-C-T

Variant names:

• chr2-206138506-C-T
• rs2230892
• NM_005006.7:c.1371G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_005006.7(NDUFS1):​c.1371G>A​(p.Ser457Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,613,868 control chromosomes in the GnomAD database, including 265 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 33)
  • Exomes 𝑓: 0.016 (244 hom.)
• Consequence: NDUFS1 NM_005006.7 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -1.99
• Publications: 4 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 2-206138506-C-T is Benign according to our data. Variant chr2-206138506-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 138480.
• BP7: Synonymous conserved (PhyloP=-1.99 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0112 (1702/152244) while in subpopulation NFE AF = 0.0174 (1182/68028). AF 95% confidence interval is 0.0166. There are 21 homozygotes in GnomAd4. There are 774 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.1371G>A	p.Ser457Ser	synonymous	Exon 13 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.1413G>A	p.Ser471Ser	synonymous	Exon 13 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.1263G>A	p.Ser421Ser	synonymous	Exon 12 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.1371G>A	p.Ser457Ser	synonymous	Exon 13 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903706.1		c.1371G>A	p.Ser457Ser	synonymous	Exon 13 of 19	ENSP00000573765.1
	NDUFS1	ENST00000449699.5	TSL:2	c.1371G>A	p.Ser457Ser	synonymous	Exon 13 of 19	ENSP00000399912.1	P28331-1

Frequencies

GnomAD3 genomes AF: 0.0112 AC: 1702 AN: 152126 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0126

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0113 AC: 2837 AN: 251472 AF XY: 0.0114

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00980

Gnomad ASJ exome AF: 0.0297

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0156

GnomAD4 exome AF: 0.0162 AC: 23741 AN: 1461624 Hom.: 244 Cov.: 32 AF XY: 0.0161 AC XY: 11737 AN XY: 727124

African (AFR) AF: 0.00293 AC: 98 AN: 33480

American (AMR) AF: 0.0114 AC: 512 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0284 AC: 741 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39690

South Asian (SAS) AF: 0.00321 AC: 277 AN: 86254

European-Finnish (FIN) AF: 0.00266 AC: 142 AN: 53414

Middle Eastern (MID) AF: 0.0135 AC: 78 AN: 5766

European-Non Finnish (NFE) AF: 0.0189 AC: 21006 AN: 1111780

Other (OTH) AF: 0.0147 AC: 885 AN: 60388

GnomAD4 genome AF: 0.0112 AC: 1702 AN: 152244 Hom.: 21 Cov.: 33 AF XY: 0.0104 AC XY: 774 AN XY: 74436

African (AFR) AF: 0.00373 AC: 155 AN: 41540

American (AMR) AF: 0.0126 AC: 193 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0323 AC: 112 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4824

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10598

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1182 AN: 68028

Other (OTH) AF: 0.0123 AC: 26 AN: 2108

Alfa AF: 0.0142 Hom.: 10

Bravo AF: 0.0126

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0199

EpiControl AF: 0.0213

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Leigh syndrome (1)
-	1	-	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.55
DANN	Benign	0.42
PhyloP100		-2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

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: rs2230892; hg19: chr2-207003230;