19-1383551-G-C

Variant names:

• chr19-1383551-G-C
• rs117758624
• ENST00000546283.5:c.-277G>C

Variant summary

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

The ENST00000546283.5(NDUFS7):​c.-277G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 913,788 control chromosomes in the GnomAD database, including 1,091 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (162 hom., cov: 33)
  • Exomes 𝑓: 0.047 (929 hom.)
• Consequence: NDUFS7 ENST00000546283.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -6.12
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 19-1383551-G-C is Benign according to our data. Variant chr19-1383551-G-C is described in ClinVar as Benign. ClinVar VariationId is 672592.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 = 0.0362 (5510/152354) while in subpopulation SAS AF = 0.0511 (247/4834). AF 95% confidence interval is 0.0466. There are 162 homozygotes in GnomAd4. There are 2746 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 162 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.-277G>C		5_prime_UTR	Exon 1 of 8	ENSP00000440348.1	O75251-2

Frequencies

GnomAD3 genomes AF: 0.0362 AC: 5509 AN: 152236 Hom.: 162 Cov.: 33

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0499

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0775

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0480

Gnomad OTH AF: 0.0454

GnomAD4 exome AF: 0.0466 AC: 35478 AN: 761434 Hom.: 929 Cov.: 10 AF XY: 0.0469 AC XY: 18016 AN XY: 383762

African (AFR) AF: 0.00976 AC: 147 AN: 15062

American (AMR) AF: 0.0262 AC: 344 AN: 13146

Ashkenazi Jewish (ASJ) AF: 0.0475 AC: 605 AN: 12726

East Asian (EAS) AF: 0.000296 AC: 4 AN: 13524

South Asian (SAS) AF: 0.0492 AC: 2947 AN: 59910

European-Finnish (FIN) AF: 0.0794 AC: 1090 AN: 13724

Middle Eastern (MID) AF: 0.0475 AC: 102 AN: 2146

European-Non Finnish (NFE) AF: 0.0481 AC: 28946 AN: 601314

Other (OTH) AF: 0.0433 AC: 1293 AN: 29882

GnomAD4 genome AF: 0.0362 AC: 5510 AN: 152354 Hom.: 162 Cov.: 33 AF XY: 0.0369 AC XY: 2746 AN XY: 74506

African (AFR) AF: 0.0111 AC: 460 AN: 41596

American (AMR) AF: 0.0285 AC: 437 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0499 AC: 173 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5186

South Asian (SAS) AF: 0.0511 AC: 247 AN: 4834

European-Finnish (FIN) AF: 0.0775 AC: 823 AN: 10620

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0480 AC: 3262 AN: 68020

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0170 Hom.: 14

Bravo AF: 0.0323

Asia WGS AF: 0.0180 AC: 65 AN: 3478

ClinVar

ClinVar submissions

Significance: 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	-0.47
CADD	Benign	0.0010
DANN	Benign	0.42
PhyloP100		-6.1
PromoterAI		0.10	Neutral
Mutation Taster		=300/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs117758624; hg19: chr19-1383550;