rs114400263

Variant names:

• chr19-1383644-A-G
• rs114400263
• ENST00000546283.5:c.-220+36A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1383644-A-G
• chr19-1383644-A-C
• chr19-1383644-A-T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The ENST00000546283.5(NDUFS7):​c.-220+36A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00172 in 1,482,318 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (27 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (14 hom.)
• Consequence: NDUFS7 ENST00000546283.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.64
• 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

TRF-GAA1-6 (HGNC:34873):

TRN-GTT2-6 (HGNC:34758):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-1383644-A-G is Benign according to our data. Variant chr19-1383644-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1209258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00895 (1363/152314) while in subpopulation AFR AF = 0.0309 (1286/41578). AF 95% confidence interval is 0.0295. There are 27 homozygotes in GnomAd4. There are 642 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 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.-220+36A>G		intron	N/A	ENSP00000440348.1	O75251-2
	NDUFS7	ENST00000930043.1		c.-283A>G		upstream_gene	N/A	ENSP00000600102.1
	NDUFS7	ENST00000543289.5	TSL:2	n.-246A>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00891 AC: 1356 AN: 152196 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.00478

GnomAD4 exome AF: 0.000887 AC: 1180 AN: 1330004 Hom.: 14 Cov.: 29 AF XY: 0.000790 AC XY: 518 AN XY: 655708

African (AFR) AF: 0.0296 AC: 877 AN: 29624

American (AMR) AF: 0.00140 AC: 43 AN: 30778

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23448

East Asian (EAS) AF: 0.0000312 AC: 1 AN: 32020

South Asian (SAS) AF: 0.000104 AC: 8 AN: 76590

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29414

Middle Eastern (MID) AF: 0.00152 AC: 7 AN: 4612

European-Non Finnish (NFE) AF: 0.000126 AC: 132 AN: 1048942

Other (OTH) AF: 0.00205 AC: 112 AN: 54576

GnomAD4 genome AF: 0.00895 AC: 1363 AN: 152314 Hom.: 27 Cov.: 33 AF XY: 0.00862 AC XY: 642 AN XY: 74482

African (AFR) AF: 0.0309 AC: 1286 AN: 41578

American (AMR) AF: 0.00327 AC: 50 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 68006

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.000268 Hom.: 0

Bravo AF: 0.00972

Asia WGS AF: 0.00173 AC: 6 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	-0.44
CADD	Benign	0.060
DANN	Benign	0.33
PhyloP100		-4.6
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs114400263; hg19: chr19-1383643;