2-206123747-G-T

Variant names:

• chr2-206123747-G-T
• rs561980718
• NM_005006.7:c.*438C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005006.7(NDUFS1):​c.*438C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000148 in 6,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).

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.*438C>A		3_prime_UTR	Exon 19 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.*438C>A		3_prime_UTR	Exon 19 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.*438C>A		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.*438C>A		3_prime_UTR	Exon 19 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903709.1		c.*438C>A		3_prime_UTR	Exon 18 of 18	ENSP00000573768.1
	NDUFS1	ENST00000938122.1		c.*438C>A		3_prime_UTR	Exon 20 of 20	ENSP00000608181.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.000148 AC: 1 AN: 6758 Hom.: 0 Cov.: 0 AF XY: 0.000278 AC XY: 1 AN XY: 3600

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

African (AFR) AF: 0.00 AC: 0 AN: 46

American (AMR) AF: 0.00 AC: 0 AN: 774

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 76

East Asian (EAS) AF: 0.00 AC: 0 AN: 246

South Asian (SAS) AF: 0.00156 AC: 1 AN: 642

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 188

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4474

Other (OTH) AF: 0.00 AC: 0 AN: 304

⚠️ 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 Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	2.3
DANN	Benign	0.57
PhyloP100		-0.054

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: rs561980718; hg19: chr2-206988471;