chr2-206124027-A-G

Position:

• chr2-206124027-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000233190.11(NDUFS1):​c.*158T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0307 in 617,484 control chromosomes in the GnomAD database, including 375 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (86 hom., cov: 33)
  • Exomes 𝑓: 0.032 (289 hom.)
• Consequence: NDUFS1 ENST00000233190.11 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.03

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 2-206124027-A-G is Benign according to our data. Variant chr2-206124027-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 333776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0261 (3975/152326) while in subpopulation SAS AF= 0.0431 (208/4826). AF 95% confidence interval is 0.0383. There are 86 homozygotes in gnomad4. There are 1986 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 86 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS1	NM_005006.7	c.*158T>C		3_prime_UTR_variant	19/19	ENST00000233190.11	NP_004997.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS1	ENST00000233190.11	c.*158T>C		3_prime_UTR_variant	19/19	1	NM_005006.7	ENSP00000233190	P1
NDUFS1	ENST00000423725.5	c.*158T>C		3_prime_UTR_variant	18/18	2		ENSP00000397760
NDUFS1	ENST00000440274.5	c.*158T>C		3_prime_UTR_variant	18/18	2		ENSP00000409766
NDUFS1	ENST00000457011.5	c.*158T>C		3_prime_UTR_variant	15/15	2		ENSP00000400976

Frequencies

GnomAD3 genomes AF: 0.0261 AC: 3968 AN: 152208 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.00651

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.0342

Gnomad SAS AF: 0.0433

Gnomad FIN AF: 0.0284

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0345

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.0322 AC: 14974 AN: 465158 Hom.: 289 Cov.: 5 AF XY: 0.0330 AC XY: 8143 AN XY: 246396

Gnomad4 AFR exome AF: 0.00648

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.0312

Gnomad4 SAS exome AF: 0.0436

Gnomad4 FIN exome AF: 0.0249

Gnomad4 NFE exome AF: 0.0339

Gnomad4 OTH exome AF: 0.0301

GnomAD4 genome AF: 0.0261 AC: 3975 AN: 152326 Hom.: 86 Cov.: 33 AF XY: 0.0267 AC XY: 1986 AN XY: 74486

Gnomad4 AFR AF: 0.00676

Gnomad4 AMR AF: 0.0218

Gnomad4 ASJ AF: 0.0369

Gnomad4 EAS AF: 0.0341

Gnomad4 SAS AF: 0.0431

Gnomad4 FIN AF: 0.0284

Gnomad4 NFE AF: 0.0345

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0310 Hom.: 10

Bravo AF: 0.0249

Asia WGS AF: 0.0420 AC: 147 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex I deficiency, nuclear type 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Leigh syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	12
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

Publications

LitVar

Other links and lift over

dbSNP: rs3770989; hg19: chr2-206988751;