Genetic Variant ENST00000546283:c.-277G>C (chr19-1383551-G-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000546283(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_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -6.12

Variant links:

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 links:

TRN-GTT2-6 (HGNC:34758):

TRN-GTT2-6 links:

TRF-GAA1-6 (HGNC:34873):

TRF-GAA1-6 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 162 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRN-GTT2-6	unassigned_transcript_3182	c.-12G>C		upstream_gene_variant
TRF-GAA1-6	unassigned_transcript_3181	c.-117C>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFS7	ENST00000546283 link	c.-277G>C		5_prime_UTR_variant	Exon 1 of 8	2		ENSP00000440348.1		O75251-2

Frequencies

GnomAD3 genomes

AF:

0.0362

AC:

5509

AN:

152236

Hom.:

162

Cov.:

show subpopulations

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.:

AF XY:

0.0469

AC XY:

18016

AN XY:

383762

show subpopulations

Gnomad4 AFR exome

AF:

0.00976

Gnomad4 AMR exome

AF:

0.0262

Gnomad4 ASJ exome

AF:

0.0475

Gnomad4 EAS exome

AF:

0.000296

Gnomad4 SAS exome

AF:

0.0492

Gnomad4 FIN exome

AF:

0.0794

Gnomad4 NFE exome

AF:

0.0481

Gnomad4 OTH exome

AF:

0.0433

GnomAD4 genome

AF:

0.0362

AC:

5510

AN:

152354

Hom.:

162

Cov.:

AF XY:

0.0369

AC XY:

2746

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.0285

Gnomad4 ASJ

AF:

0.0499

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0511

Gnomad4 FIN

AF:

0.0775

Gnomad4 NFE

AF:

0.0480

Gnomad4 OTH

AF:

0.0449

Alfa

AF:

0.0170

Hom.:

Bravo

AF:

0.0323

Asia WGS

AF:

0.0180

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.0010

DANN

Benign

0.42

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over