2-206123786-C-T

Variant names:

• chr2-206123786-C-T
• rs77000728
• NM_005006.7:c.*399G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005006.7(NDUFS1):​c.*399G>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 0.0146 in 167,506 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.772
• Publications: 1 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=-0.86).
• BP6: Variant 2-206123786-C-T is Benign according to our data. Variant chr2-206123786-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0528 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS1	NM_005006.7	MANE Select	c.*399G>A		3_prime_UTR	Exon 19 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.*399G>A		3_prime_UTR	Exon 19 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.*399G>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.*399G>A		3_prime_UTR	Exon 19 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903709.1		c.*399G>A		3_prime_UTR	Exon 18 of 18	ENSP00000573768.1
	NDUFS1	ENST00000938122.1		c.*399G>A		3_prime_UTR	Exon 20 of 20	ENSP00000608181.1

Frequencies

GnomAD3 genomes AF: 0.0159 AC: 2412 AN: 152002 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.0547

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.0138

GnomAD4 exome AF: 0.00143 AC: 22 AN: 15386 Hom.: 0 Cov.: 0 AF XY: 0.00162 AC XY: 13 AN XY: 8042

African (AFR) AF: 0.0455 AC: 9 AN: 198

American (AMR) AF: 0.00413 AC: 6 AN: 1454

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 280

East Asian (EAS) AF: 0.00 AC: 0 AN: 700

South Asian (SAS) AF: 0.00 AC: 0 AN: 1502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 40

European-Non Finnish (NFE) AF: 0.000202 AC: 2 AN: 9886

Other (OTH) AF: 0.00633 AC: 5 AN: 790

GnomAD4 genome AF: 0.0159 AC: 2419 AN: 152120 Hom.: 58 Cov.: 32 AF XY: 0.0155 AC XY: 1155 AN XY: 74386

African (AFR) AF: 0.0547 AC: 2270 AN: 41484

American (AMR) AF: 0.00609 AC: 93 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10566

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 68006

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.00765 Hom.: 4

Bravo AF: 0.0179

Asia WGS AF: 0.00260 AC: 9 AN: 3474

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	-0.86
CADD	Benign	1.9
DANN	Benign	0.65
PhyloP100		-0.77
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: rs77000728; hg19: chr2-206988510;