2-206123849-C-A

Variant names:

• chr2-206123849-C-A
• rs1044120
• NM_005006.7:c.*336G>T

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.*336G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 205,206 control chromosomes in the GnomAD database, including 27,059 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21981 hom., cov: 32)
  • Exomes 𝑓: 0.42 (5078 hom.)
• Consequence: NDUFS1 NM_005006.7 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0460
• Publications: 16 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=-0.89).
• BP6: Variant 2-206123849-C-A is Benign according to our data. Variant chr2-206123849-C-A is described in ClinVar as Benign. ClinVar VariationId is 333774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.727 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.*336G>T		3_prime_UTR	Exon 19 of 19	NP_004997.4
	NDUFS1	NM_001199984.2		c.*336G>T		3_prime_UTR	Exon 19 of 19	NP_001186913.1	P28331-2
	NDUFS1	NM_001199981.2		c.*336G>T		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.*336G>T		3_prime_UTR	Exon 19 of 19	ENSP00000233190.5	P28331-1
	NDUFS1	ENST00000903709.1		c.*336G>T		3_prime_UTR	Exon 18 of 18	ENSP00000573768.1
	NDUFS1	ENST00000938122.1		c.*336G>T		3_prime_UTR	Exon 20 of 20	ENSP00000608181.1

Frequencies

GnomAD3 genomes AF: 0.517 AC: 78503 AN: 151750 Hom.: 21945 Cov.: 32

Gnomad AFR AF: 0.734

Gnomad AMI AF: 0.260

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.529

Gnomad EAS AF: 0.248

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.518

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.427

Gnomad OTH AF: 0.527

GnomAD4 exome AF: 0.422 AC: 22488 AN: 53336 Hom.: 5078 Cov.: 0 AF XY: 0.415 AC XY: 11492 AN XY: 27716

African (AFR) AF: 0.723 AC: 1246 AN: 1724

American (AMR) AF: 0.450 AC: 1201 AN: 2666

Ashkenazi Jewish (ASJ) AF: 0.521 AC: 966 AN: 1854

East Asian (EAS) AF: 0.226 AC: 850 AN: 3766

South Asian (SAS) AF: 0.303 AC: 797 AN: 2632

European-Finnish (FIN) AF: 0.485 AC: 983 AN: 2026

Middle Eastern (MID) AF: 0.567 AC: 144 AN: 254

European-Non Finnish (NFE) AF: 0.421 AC: 14761 AN: 35040

Other (OTH) AF: 0.456 AC: 1540 AN: 3374

GnomAD4 genome AF: 0.517 AC: 78592 AN: 151870 Hom.: 21981 Cov.: 32 AF XY: 0.515 AC XY: 38219 AN XY: 74202

African (AFR) AF: 0.734 AC: 30432 AN: 41444

American (AMR) AF: 0.491 AC: 7469 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.529 AC: 1836 AN: 3470

East Asian (EAS) AF: 0.248 AC: 1283 AN: 5166

South Asian (SAS) AF: 0.332 AC: 1599 AN: 4810

European-Finnish (FIN) AF: 0.518 AC: 5455 AN: 10526

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.427 AC: 29026 AN: 67924

Other (OTH) AF: 0.523 AC: 1103 AN: 2110

Alfa AF: 0.448 Hom.: 15824

Bravo AF: 0.522

Asia WGS AF: 0.304 AC: 1054 AN: 3468

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.5
DANN	Benign	0.41
PhyloP100		0.046
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs1044120; hg19: chr2-206988573;