rs2074897

Variant names:

• chr19-1391236-G-A
• rs2074897
• NM_024407.5:c.455+71G>A

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.455+71G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.444 in 1,539,078 control chromosomes in the GnomAD database, including 158,271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (11075 hom., cov: 31)
  • Exomes 𝑓: 0.46 (147196 hom.)
• Consequence: NDUFS7 NM_024407.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.741
• Publications: 10 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-1391236-G-A is Benign according to our data. Variant chr19-1391236-G-A is described in ClinVar as Benign. ClinVar VariationId is 1185398.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.47 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFS7	NM_024407.5	c.455+71G>A		intron_variant	Intron 6 of 7	ENST00000233627.14	NP_077718.3
NDUFS7	NM_001363602.2	c.455+71G>A		intron_variant	Intron 6 of 7		NP_001350531.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000233627.14	c.455+71G>A		intron_variant	Intron 6 of 7	1	NM_024407.5	ENSP00000233627.9

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52740 AN: 151828 Hom.: 11078 Cov.: 31

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.658

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.480

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.408

Gnomad FIN AF: 0.380

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.388

GnomAD4 exome AF: 0.455 AC: 631212 AN: 1387130 Hom.: 147196 AF XY: 0.456 AC XY: 313328 AN XY: 687570

African (AFR) AF: 0.0871 AC: 2764 AN: 31726

American (AMR) AF: 0.390 AC: 15175 AN: 38892

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 12044 AN: 25266

East Asian (EAS) AF: 0.316 AC: 11766 AN: 37192

South Asian (SAS) AF: 0.431 AC: 34878 AN: 80922

European-Finnish (FIN) AF: 0.383 AC: 19064 AN: 49806

Middle Eastern (MID) AF: 0.517 AC: 2221 AN: 4294

European-Non Finnish (NFE) AF: 0.479 AC: 508072 AN: 1061480

Other (OTH) AF: 0.438 AC: 25228 AN: 57552

GnomAD4 genome AF: 0.347 AC: 52730 AN: 151948 Hom.: 11075 Cov.: 31 AF XY: 0.343 AC XY: 25470 AN XY: 74242

African (AFR) AF: 0.100 AC: 4168 AN: 41490

American (AMR) AF: 0.367 AC: 5600 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.480 AC: 1664 AN: 3470

East Asian (EAS) AF: 0.296 AC: 1515 AN: 5124

South Asian (SAS) AF: 0.410 AC: 1971 AN: 4804

European-Finnish (FIN) AF: 0.380 AC: 4015 AN: 10570

Middle Eastern (MID) AF: 0.510 AC: 150 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32241 AN: 67904

Other (OTH) AF: 0.382 AC: 807 AN: 2110

Alfa AF: 0.395 Hom.: 2141

Bravo AF: 0.337

Asia WGS AF: 0.306 AC: 1063 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mitochondrial complex I deficiency, nuclear type 3 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.7
DANN	Benign	0.78
PhyloP100		0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs2074897; hg19: chr19-1391235; COSMIC: COSV52040979; COSMIC: COSV52040979;