rs104893899

Variant names:

• chr5-53560706-G-A
• rs104893899
• NM_002495.4:c.44G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-53560706-G-A
• chr5-53560706-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002495.4(NDUFS4):​c.44G>A​(p.Trp15*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFS4 NM_002495.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0350
• Publications: 9 publications found

Genes affected

NDUFS4 (HGNC:7711): (NADH:ubiquinone oxidoreductase subunit S4) This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

NDUFS4 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P
• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• mitochondrial complex I deficiency, nuclear type 1

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• mitochondrial complex I deficiency, nuclear type

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 32 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-53560706-G-A is Pathogenic according to our data. Variant chr5-53560706-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6890.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002495.4. 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
	NDUFS4	NM_002495.4	MANE Select	c.44G>A	p.Trp15*	stop_gained	Exon 1 of 5	NP_002486.1	A0A0S2Z433
	NDUFS4	NM_001318051.2		c.44G>A	p.Trp15*	stop_gained	Exon 1 of 4	NP_001304980.1
	NDUFS4	NR_134473.2		n.68G>A		non_coding_transcript_exon	Exon 1 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.44G>A	p.Trp15*	stop_gained	Exon 1 of 5	ENSP00000296684.5	O43181
	NDUFS4	ENST00000506974.5	TSL:1	n.44G>A		non_coding_transcript_exon	Exon 1 of 6	ENSP00000425967.1	D6RI09
	NDUFS4	ENST00000856911.1		c.44G>A	p.Trp15*	stop_gained	Exon 1 of 4	ENSP00000526970.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	35
DANN	Benign	0.95
Eigen	Benign	0.13
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.29	N
PhyloP100		-0.035
Vest4		0.57
GERP RS		-1.2
PromoterAI		-0.064	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=6/194	disease causing (ClinVar)

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: rs104893899; hg19: chr5-52856536;