rs11668291

Variant names:

• chr19-1384247-C-T
• rs11668291
• NM_024407.5:c.16+305C>T

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+305C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0272 in 462,998 control chromosomes in the GnomAD database, including 228 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 33)
  • Exomes 𝑓: 0.028 (165 hom.)
• Consequence: NDUFS7 NM_024407.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.931
• Publications: 2 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=-0.94).
• BP6: Variant 19-1384247-C-T is Benign according to our data. Variant chr19-1384247-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 671566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0246 (3743/152298) while in subpopulation NFE AF = 0.0347 (2362/68018). AF 95% confidence interval is 0.0336. There are 63 homozygotes in GnomAd4. There are 1798 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 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+305C>T		intron	N/A	NP_077718.3
	NDUFS7	NM_001363602.2		c.16+305C>T		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+305C>T		intron	N/A	ENSP00000233627.9	O75251-1
	NDUFS7	ENST00000874016.1		c.230+91C>T		intron	N/A	ENSP00000544075.1
	NDUFS7	ENST00000874018.1		c.230+91C>T		intron	N/A	ENSP00000544077.1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3745 AN: 152180 Hom.: 63 Cov.: 33

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0547

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0101

Gnomad FIN AF: 0.0362

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0347

Gnomad OTH AF: 0.0378

GnomAD4 exome AF: 0.0285 AC: 8840 AN: 310700 Hom.: 165 AF XY: 0.0287 AC XY: 4680 AN XY: 163190

African (AFR) AF: 0.00913 AC: 57 AN: 6244

American (AMR) AF: 0.0170 AC: 124 AN: 7274

Ashkenazi Jewish (ASJ) AF: 0.0573 AC: 553 AN: 9654

East Asian (EAS) AF: 0.00 AC: 0 AN: 20558

South Asian (SAS) AF: 0.0120 AC: 310 AN: 25808

European-Finnish (FIN) AF: 0.0314 AC: 782 AN: 24870

Middle Eastern (MID) AF: 0.0408 AC: 60 AN: 1470

European-Non Finnish (NFE) AF: 0.0328 AC: 6439 AN: 196034

Other (OTH) AF: 0.0274 AC: 515 AN: 18788

GnomAD4 genome AF: 0.0246 AC: 3743 AN: 152298 Hom.: 63 Cov.: 33 AF XY: 0.0241 AC XY: 1798 AN XY: 74472

African (AFR) AF: 0.00597 AC: 248 AN: 41562

American (AMR) AF: 0.0248 AC: 380 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0547 AC: 190 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0101 AC: 49 AN: 4828

European-Finnish (FIN) AF: 0.0362 AC: 384 AN: 10612

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0347 AC: 2362 AN: 68018

Other (OTH) AF: 0.0374 AC: 79 AN: 2112

Alfa AF: 0.0295 Hom.: 5

Bravo AF: 0.0223

Asia WGS AF: 0.00664 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	-0.94
CADD	Benign	2.8
DANN	Benign	0.73
PhyloP100		-0.93
PromoterAI		-0.030	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: rs11668291; hg19: chr19-1384246;