NM_005006.7:c.*93dupA

Variant names:

• chr2-206124091-A-AT
• rs200446477
• NM_005006.7:c.*93dupA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_005006.7(NDUFS1):​c.*93dupA 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 NM_005006.7 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.29
• Publications: 0 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: Likely_benign. The variant received -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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 3 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.*93dupA		3_prime_UTR	Exon 19 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.*93dupA		3_prime_UTR	Exon 19 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.*93dupA		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.*93dupA		3_prime_UTR	Exon 19 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903707.1		c.*93dupA		splice_region	Exon 18 of 18	ENSP00000573766.1
	NDUFS1	ENST00000903706.1		c.*93dupA		3_prime_UTR	Exon 19 of 19	ENSP00000573765.1

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00721 AC: 114 AN: 15808

American (AMR) AF: 0.00132 AC: 40 AN: 30204

Ashkenazi Jewish (ASJ) AF: 0.000369 AC: 7 AN: 18954

East Asian (EAS) AF: 0.000249 AC: 8 AN: 32134

South Asian (SAS) AF: 0.00170 AC: 102 AN: 59998

European-Finnish (FIN) AF: 0.000920 AC: 44 AN: 47822

Middle Eastern (MID) AF: 0.00174 AC: 7 AN: 4020

European-Non Finnish (NFE) AF: 0.00206 AC: 834 AN: 405470

Other (OTH) AF: 0.00141 AC: 46 AN: 32648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.00689 AC: 285 AN: 41344

American (AMR) AF: 0.00119 AC: 18 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5144

South Asian (SAS) AF: 0.00167 AC: 8 AN: 4796

European-Finnish (FIN) AF: 0.000287 AC: 3 AN: 10470

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00136 AC: 92 AN: 67850

Other (OTH) AF: 0.00192 AC: 4 AN: 2088

Alfa AF: 0.000271 Hom.: 0

Bravo AF: 0.00288

Asia WGS AF: 0.00173 AC: 6 AN: 3472

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Leigh syndrome (1)
-	1	-	Mitochondrial complex I deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
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: rs200446477; hg19: chr2-206988815; COSMIC: COSV99261690; COSMIC: COSV99261690;