19-1391362-A-G

Variant names:

• chr19-1391362-A-G
• rs2074898
• NM_024407.5:c.455+197A>G

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+197A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.647 in 151,800 control chromosomes in the GnomAD database, including 31,867 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.65 (31867 hom., cov: 31)
• Consequence: NDUFS7 NM_024407.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.46
• 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=-1.03).
• BP6: Variant 19-1391362-A-G is Benign according to our data. Variant chr19-1391362-A-G is described in ClinVar as Benign. ClinVar VariationId is 683141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.683 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS7	NM_024407.5	MANE Select	c.455+197A>G		intron	N/A	NP_077718.3
	NDUFS7	NM_001363602.2		c.455+197A>G		intron	N/A	NP_001350531.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS7	ENST00000233627.14	TSL:1 MANE Select	c.455+197A>G		intron	N/A	ENSP00000233627.9
	NDUFS7	ENST00000414651.3	TSL:5	c.545+197A>G		intron	N/A	ENSP00000406630.2
	NDUFS7	ENST00000313408.11	TSL:2	c.455+197A>G		intron	N/A	ENSP00000364262.5

Frequencies

GnomAD3 genomes AF: 0.647 AC: 98187 AN: 151680 Hom.: 31830 Cov.: 31

Gnomad AFR AF: 0.664

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.664

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.574

Gnomad SAS AF: 0.701

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.650

Gnomad OTH AF: 0.667

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.647 AC: 98286 AN: 151800 Hom.: 31867 Cov.: 31 AF XY: 0.642 AC XY: 47598 AN XY: 74140

African (AFR) AF: 0.664 AC: 27483 AN: 41396

American (AMR) AF: 0.663 AC: 10123 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2208 AN: 3470

East Asian (EAS) AF: 0.574 AC: 2957 AN: 5152

South Asian (SAS) AF: 0.702 AC: 3369 AN: 4796

European-Finnish (FIN) AF: 0.540 AC: 5673 AN: 10512

Middle Eastern (MID) AF: 0.684 AC: 201 AN: 294

European-Non Finnish (NFE) AF: 0.650 AC: 44144 AN: 67898

Other (OTH) AF: 0.670 AC: 1408 AN: 2102

Alfa AF: 0.636 Hom.: 4408

Bravo AF: 0.653

Asia WGS AF: 0.643 AC: 2234 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.18
DANN	Benign	0.51
PhyloP100		-2.5
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: rs2074898; hg19: chr19-1391361;