19-1386644-C-G

Position:

• chr19-1386644-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_024407.5(NDUFS7):​c.17-1167C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFS7 NM_024407.5 intron
• Scores: Splicing: ADA: 0.00001597
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -1.72

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]

ENSG00000280486 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1386644-C-G is Pathogenic according to our data. Variant chr19-1386644-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 7683.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NDUFS7	NM_024407.5	c.17-1167C>G		intron_variant		ENST00000233627.14	NP_077718.3
NDUFS7	NM_001363602.2	c.17-1167C>G		intron_variant			NP_001350531.1
NDUFS7	XM_017026768.3	c.17-1167C>G		intron_variant			XP_016882257.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000233627.14	c.17-1167C>G		intron_variant		1	NM_024407.5	ENSP00000233627.9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leigh syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 02, 2024

Variant summary: NDUFS7 c.17-1167C>G is located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Four predict the variant strengthens a cryptic 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 31372 control chromosomes. c.17-1167C>G has been reported in the literature in two homozygous siblings affected with Leigh Syndrome (Lebon_2007). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a defect in mitochondrial complex I assembly (Lebon_2007) and using cell lines derived from these patients, Lebon_2015 showed that the variant had 35% NADH ubiquinone reductase activity compared to wildtype. The following publications have been ascertained in the context of this evaluation (PMID: 17604671, 26024641). ClinVar contains an entry for this variant (Variation ID: 7683). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Mitochondrial complex 1 deficiency, nuclear type 3 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.61
DANN	Benign	0.35

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.27		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1568985256; hg19: chr19-1386643;