chr19-1383562-C-T

Variant names:

• chr19-1383562-C-T
• rs115444924
• ENST00000546283.5:c.-266C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The ENST00000546283.5(NDUFS7):​c.-266C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,054,606 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0075 (15 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (9 hom.)
• Consequence: NDUFS7 ENST00000546283.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.72
• 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

TRN-GTT2-6 (HGNC:34758):

TRF-GAA1-6 (HGNC:34873):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 19-1383562-C-T is Benign according to our data. Variant chr19-1383562-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1205191.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00753 (1147/152352) while in subpopulation AFR AF = 0.0252 (1047/41574). AF 95% confidence interval is 0.0239. There are 15 homozygotes in GnomAd4. There are 545 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000546283.5. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS7	ENST00000546283.5	TSL:2	c.-266C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	ENSP00000440348.1	O75251-2
	NDUFS7	ENST00000546283.5	TSL:2	c.-266C>T		5_prime_UTR	Exon 1 of 8	ENSP00000440348.1	O75251-2

Frequencies

GnomAD3 genomes AF: 0.00752 AC: 1145 AN: 152234 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0252

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00418

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.000833 AC: 752 AN: 902254 Hom.: 9 Cov.: 12 AF XY: 0.000794 AC XY: 358 AN XY: 450928

African (AFR) AF: 0.0243 AC: 439 AN: 18070

American (AMR) AF: 0.00273 AC: 41 AN: 15010

Ashkenazi Jewish (ASJ) AF: 0.000204 AC: 3 AN: 14710

East Asian (EAS) AF: 0.00128 AC: 20 AN: 15588

South Asian (SAS) AF: 0.000297 AC: 19 AN: 64064

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 14926

Middle Eastern (MID) AF: 0.00121 AC: 3 AN: 2484

European-Non Finnish (NFE) AF: 0.000240 AC: 173 AN: 722102

Other (OTH) AF: 0.00153 AC: 54 AN: 35300

GnomAD4 genome AF: 0.00753 AC: 1147 AN: 152352 Hom.: 15 Cov.: 33 AF XY: 0.00732 AC XY: 545 AN XY: 74500

African (AFR) AF: 0.0252 AC: 1047 AN: 41574

American (AMR) AF: 0.00418 AC: 64 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5182

South Asian (SAS) AF: 0.000827 AC: 4 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68034

Other (OTH) AF: 0.00662 AC: 14 AN: 2116

Alfa AF: 0.0000686 Hom.: 0

Bravo AF: 0.00870

Asia WGS AF: 0.00491 AC: 17 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	0.0020
DANN	Benign	0.93
PhyloP100		-4.7
PromoterAI		-0.031	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs115444924; hg19: chr19-1383561;