rs1142530

Variant names:

• chr19-1388539-C-T
• rs1142530
• NM_024407.5:c.68C>T

Variant summary

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

The NM_024407.5(NDUFS7):​c.68C>T​(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.592 in 1,610,648 control chromosomes in the GnomAD database, including 287,790 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21647 hom., cov: 33)
  • Exomes 𝑓: 0.60 (266143 hom.)
• Consequence: NDUFS7 NM_024407.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.979
• Publications: 53 publications found

Genes affected

NDUFS7 (HGNC:7714): (NADH:ubiquinone oxidoreductase core subunit S7) This gene encodes a protein that is a subunit of one of the complexes that forms the mitochondrial respiratory chain. This protein is one of over 40 subunits found in complex I, the nicotinamide adenine dinucleotide (NADH):ubiquinone oxidoreductase. This complex functions in the transfer of electrons from NADH to the respiratory chain, and ubiquinone is believed to be the immediate electron acceptor for the enzyme. Mutations in this gene cause Leigh syndrome due to mitochondrial complex I deficiency, a severe neurological disorder that results in bilaterally symmetrical necrotic lesions in subcortical brain regions. [provided by RefSeq, Jul 2008]

NDUFS7 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE 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

ENSG00000280486 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=1.1169489E-5).
• BP6: Variant 19-1388539-C-T is Benign according to our data. Variant chr19-1388539-C-T is described in ClinVar as Benign. ClinVar VariationId is 129702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.619 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024407.5. 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
	NDUFS7	NM_024407.5	MANE Select	c.68C>T	p.Pro23Leu	missense	Exon 3 of 8	NP_077718.3
	NDUFS7	NM_001363602.2		c.68C>T	p.Pro23Leu	missense	Exon 3 of 8	NP_001350531.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS7	ENST00000233627.14	TSL:1 MANE Select	c.68C>T	p.Pro23Leu	missense	Exon 3 of 8	ENSP00000233627.9
	NDUFS7	ENST00000874016.1		c.404C>T	p.Pro135Leu	missense	Exon 4 of 9	ENSP00000544075.1
	NDUFS7	ENST00000874018.1		c.404C>T	p.Pro135Leu	missense	Exon 3 of 8	ENSP00000544077.1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79346 AN: 151926 Hom.: 21646 Cov.: 33

Gnomad AFR AF: 0.373

Gnomad AMI AF: 0.771

Gnomad AMR AF: 0.488

Gnomad ASJ AF: 0.601

Gnomad EAS AF: 0.322

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.526

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.624

Gnomad OTH AF: 0.570

GnomAD2 exomes AF: 0.546 AC: 134740 AN: 246744 AF XY: 0.556

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.499

Gnomad ASJ exome AF: 0.606

Gnomad EAS exome AF: 0.299

Gnomad FIN exome AF: 0.528

Gnomad NFE exome AF: 0.614

Gnomad OTH exome AF: 0.566

GnomAD4 exome AF: 0.600 AC: 874836 AN: 1458606 Hom.: 266143 Cov.: 58 AF XY: 0.601 AC XY: 435964 AN XY: 725652

African (AFR) AF: 0.365 AC: 12181 AN: 33410

American (AMR) AF: 0.497 AC: 22196 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 15765 AN: 26104

East Asian (EAS) AF: 0.344 AC: 13666 AN: 39676

South Asian (SAS) AF: 0.580 AC: 49958 AN: 86122

European-Finnish (FIN) AF: 0.528 AC: 27641 AN: 52370

Middle Eastern (MID) AF: 0.634 AC: 2885 AN: 4548

European-Non Finnish (NFE) AF: 0.625 AC: 695213 AN: 1111528

Other (OTH) AF: 0.587 AC: 35331 AN: 60204

GnomAD4 genome AF: 0.522 AC: 79373 AN: 152042 Hom.: 21647 Cov.: 33 AF XY: 0.513 AC XY: 38160 AN XY: 74316

African (AFR) AF: 0.373 AC: 15455 AN: 41458

American (AMR) AF: 0.487 AC: 7447 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.601 AC: 2084 AN: 3470

East Asian (EAS) AF: 0.321 AC: 1657 AN: 5156

South Asian (SAS) AF: 0.555 AC: 2680 AN: 4828

European-Finnish (FIN) AF: 0.526 AC: 5569 AN: 10584

Middle Eastern (MID) AF: 0.650 AC: 191 AN: 294

European-Non Finnish (NFE) AF: 0.624 AC: 42388 AN: 67954

Other (OTH) AF: 0.568 AC: 1200 AN: 2112

Alfa AF: 0.584 Hom.: 86417

Bravo AF: 0.511

TwinsUK AF: 0.628 AC: 2328

ALSPAC AF: 0.631 AC: 2430

ESP6500AA AF: 0.380 AC: 1674

ESP6500EA AF: 0.623 AC: 5353

ExAC AF: 0.543 AC: 65719

Asia WGS AF: 0.411 AC: 1428 AN: 3478

EpiCase AF: 0.621

EpiControl AF: 0.627

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Leigh syndrome (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 1 (1)
-	-	1	Mitochondrial complex I deficiency, nuclear type 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	9.0
DANN	Benign	0.66
DEOGEN2	Benign	0.0054	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.11	T
MetaRNN	Benign	0.000011	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.98
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.96	N
REVEL	Benign	0.070
Sift	Benign	0.40	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.12
MPC		0.53
ClinPred		0.0074	T
GERP RS		0.84
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.2
Varity_R		0.023
gMVP		0.44
Mutation Taster		=97/3	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: rs1142530; hg19: chr19-1388538; COSMIC: COSV52039612; COSMIC: COSV52039612;