19-19526257-G-T

Variant names:

• chr19-19526257-G-T
• rs752513525
• NM_015965.7:c.170G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_015965.7(NDUFA13):​c.170G>T​(p.Arg57Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R57H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFA13 NM_015965.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.40
• Publications: 8 publications found

Genes affected

NDUFA13 (HGNC:17194): (NADH:ubiquinone oxidoreductase subunit A13) This gene encodes a subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I), which functions in the transfer of electrons from NADH to the respiratory chain. The protein is required for complex I assembly and electron transfer activity. The protein binds the signal transducers and activators of transcription 3 (STAT3) transcription factor, and can function as a tumor suppressor. The human protein purified from mitochondria migrates at approximately 16 kDa. Transcripts originating from an upstream promoter and capable of expressing a protein with a longer N-terminus have been found, but their biological validity has not been determined. [provided by RefSeq, Oct 2009]

NDUFA13 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial complex I deficiency, nuclear type 28

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• thyroid Hurthle cell carcinoma

  Inheritance: Unknown Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000258674 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-19526257-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 132643.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015965.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA13	NM_015965.7	MANE Select	c.170G>T	p.Arg57Leu	missense	Exon 2 of 5	NP_057049.5

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA13	ENST00000507754.9	TSL:1 MANE Select	c.170G>T	p.Arg57Leu	missense	Exon 2 of 5	ENSP00000423673.1
	ENSG00000258674	ENST00000555938.1	TSL:2	c.170G>T	p.Arg57Leu	missense	Exon 2 of 7	ENSP00000452549.1
	NDUFA13	ENST00000428459.6	TSL:2	c.170G>T	p.Arg57Leu	missense	Exon 2 of 4	ENSP00000465129.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.032	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.4
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.11	T
Polyphen		0.91	P
Vest4		0.84
MutPred		0.65		Loss of methylation at K52 (P = 0.0332)
MVP		0.79
MPC		0.51
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.86
gMVP		0.88
Mutation Taster		=32/68	disease causing

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: rs752513525; hg19: chr19-19637066;