5-53683267-G-C

Variant names:

• chr5-53683267-G-C
• rs567
• NM_002495.4:c.*46G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002495.4(NDUFS4):​c.*46G>C variant causes a 3 prime UTR change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFS4 NM_002495.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.79
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).

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.*46G>C		3_prime_UTR	Exon 5 of 5	NP_002486.1	A0A0S2Z433
	NDUFS4	NM_001318051.2		c.*137G>C		3_prime_UTR	Exon 4 of 4	NP_001304980.1
	NDUFS4	NR_134473.2		n.770G>C		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFS4	ENST00000296684.10	TSL:1 MANE Select	c.*46G>C		3_prime_UTR	Exon 5 of 5	ENSP00000296684.5	O43181
	NDUFS4	ENST00000506974.5	TSL:1	n.*350G>C		non_coding_transcript_exon	Exon 6 of 6	ENSP00000425967.1	D6RI09
	NDUFS4	ENST00000506974.5	TSL:1	n.*350G>C		3_prime_UTR	Exon 6 of 6	ENSP00000425967.1	D6RI09

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 17

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.89
PhyloP100		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs567; hg19: chr5-52979097;