19-1384022-G-C

Variant names:

• chr19-1384022-G-C
• rs113443464
• NM_024407.5:c.16+80G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024407.5(NDUFS7):​c.16+80G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,462,992 control chromosomes in the GnomAD database, including 285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (22 hom., cov: 33)
  • Exomes 𝑓: 0.017 (263 hom.)
• Consequence: NDUFS7 NM_024407.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.592
• Publications: 0 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)
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• 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=-0.74).
• BP6: Variant 19-1384022-G-C is Benign according to our data. Variant chr19-1384022-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1218579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0127 (1929/152354) while in subpopulation SAS AF = 0.0259 (125/4832). AF 95% confidence interval is 0.0222. There are 22 homozygotes in GnomAd4. There are 914 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

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.16+80G>C		intron	N/A	NP_077718.3
	NDUFS7	NM_001363602.2		c.16+80G>C		intron	N/A	NP_001350531.1	F5H5N1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS7	ENST00000233627.14	TSL:1 MANE Select	c.16+80G>C		intron	N/A	ENSP00000233627.9	O75251-1
	NDUFS7	ENST00000874016.1		c.96G>C	p.Gly32Gly	synonymous	Exon 1 of 9	ENSP00000544075.1
	NDUFS7	ENST00000874018.1		c.96G>C	p.Gly32Gly	synonymous	Exon 1 of 8	ENSP00000544077.1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1930 AN: 152240 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00330

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0256

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0181

Gnomad OTH AF: 0.0191

GnomAD4 exome AF: 0.0171 AC: 22422 AN: 1310638 Hom.: 263 Cov.: 22 AF XY: 0.0174 AC XY: 11269 AN XY: 647354

African (AFR) AF: 0.00344 AC: 90 AN: 26166

American (AMR) AF: 0.0115 AC: 306 AN: 26608

Ashkenazi Jewish (ASJ) AF: 0.00952 AC: 213 AN: 22372

East Asian (EAS) AF: 0.0000913 AC: 3 AN: 32848

South Asian (SAS) AF: 0.0256 AC: 1848 AN: 72322

European-Finnish (FIN) AF: 0.00676 AC: 307 AN: 45432

Middle Eastern (MID) AF: 0.0313 AC: 121 AN: 3860

European-Non Finnish (NFE) AF: 0.0182 AC: 18646 AN: 1026666

Other (OTH) AF: 0.0163 AC: 888 AN: 54364

GnomAD4 genome AF: 0.0127 AC: 1929 AN: 152354 Hom.: 22 Cov.: 33 AF XY: 0.0123 AC XY: 914 AN XY: 74506

African (AFR) AF: 0.00327 AC: 136 AN: 41590

American (AMR) AF: 0.0181 AC: 277 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.0259 AC: 125 AN: 4832

European-Finnish (FIN) AF: 0.00508 AC: 54 AN: 10630

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0181 AC: 1234 AN: 68024

Other (OTH) AF: 0.0189 AC: 40 AN: 2114

Alfa AF: 0.0146 Hom.: 2

Bravo AF: 0.0122

Asia WGS AF: 0.00635 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.7
DANN	Benign	0.69
PhyloP100		-0.59
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=100/0	polymorphism

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: rs113443464; hg19: chr19-1384021;