1-161199375-G-T

Variant names:

• chr1-161199375-G-T
• rs3813623
• ENST00000367993.7:c.-388G>T

Variant summary

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

The NM_004550.5(NDUFS2):​c.-388G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,320 control chromosomes in the GnomAD database, including 1,445 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1445 hom., cov: 32)
  • Exomes 𝑓: 0.18 (0 hom.)
• Consequence: NDUFS2 NM_004550.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0180
• Publications: 12 publications found

Genes affected

NDUFS2 (HGNC:7708): (NADH:ubiquinone oxidoreductase core subunit S2) The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

ADAMTS4 (HGNC:220): (ADAM metallopeptidase with thrombospondin type 1 motif 4) This gene encodes a member of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) protein family. Members of this family share several distinct protein modules, including a propeptide region, a metalloproteinase domain, a disintegrin-like domain, and a thrombospondin type 1 (TS) motif. Individual members of this family differ in the number of C-terminal TS motifs, and some have unique C-terminal domains. The enzyme encoded by this gene lacks a C-terminal TS motif. The encoded preproprotein is proteolytically processed to generate the mature protease. This protease is responsible for the degradation of aggrecan, a major proteoglycan of cartilage, and brevican, a brain-specific extracellular matrix protein. The expression of this gene is upregulated in arthritic disease and this may contribute to disease progression through the degradation of aggrecan. Alternative splicing results in multiple transcript variants, at least one of which encodes an isoform that is proteolytically processed. [provided by RefSeq, Feb 2016]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 1-161199375-G-T is Benign according to our data. Variant chr1-161199375-G-T is described in ClinVar as Benign. ClinVar VariationId is 293262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004550.5. 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
	NDUFS2	NM_004550.5		c.-388G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_004541.1	O75306-1
	NDUFS2	NM_001377301.1		c.-388G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	NP_001364230.1	O75306-2
	NDUFS2	NM_004550.5		c.-388G>T		5_prime_UTR	Exon 1 of 15	NP_004541.1	O75306-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS2	ENST00000367993.7	TSL:1	c.-388G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000367993.7	TSL:1	c.-388G>T		5_prime_UTR	Exon 1 of 15	ENSP00000356972.3	O75306-1
	NDUFS2	ENST00000679176.1		c.-388G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 14	ENSP00000504170.1	O75306-2

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18650 AN: 152136 Hom.: 1449 Cov.: 32

Gnomad AFR AF: 0.0480

Gnomad AMI AF: 0.137

Gnomad AMR AF: 0.203

Gnomad ASJ AF: 0.175

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.0992

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.136

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.182 AC: 12 AN: 66 Hom.: 0 Cov.: 0 AF XY: 0.196 AC XY: 9 AN XY: 46

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.208 AC: 10 AN: 48

Other (OTH) AF: 0.00 AC: 0 AN: 6

GnomAD4 genome AF: 0.122 AC: 18637 AN: 152254 Hom.: 1445 Cov.: 32 AF XY: 0.123 AC XY: 9178 AN XY: 74454

African (AFR) AF: 0.0479 AC: 1991 AN: 41568

American (AMR) AF: 0.203 AC: 3099 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.175 AC: 606 AN: 3470

East Asian (EAS) AF: 0.328 AC: 1692 AN: 5166

South Asian (SAS) AF: 0.0978 AC: 472 AN: 4824

European-Finnish (FIN) AF: 0.103 AC: 1090 AN: 10602

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.136 AC: 9248 AN: 68014

Other (OTH) AF: 0.128 AC: 270 AN: 2114

Alfa AF: 0.124 Hom.: 636

Bravo AF: 0.129

Asia WGS AF: 0.203 AC: 704 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.82
PhyloP100		0.018
PromoterAI		-0.034	Neutral
Mutation Taster		=300/0	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: rs3813623; hg19: chr1-161169165;