19-19516253-G-C

Variant names:

• chr19-19516253-G-C
• rs137852869
• NM_015965.7:c.15G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 PP5

The NM_015965.7(NDUFA13):​c.15G>C​(p.Lys5Asn) 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NDUFA13 NM_015965.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.93
• Publications: 9 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781
• PP5: Variant 19-19516253-G-C is Pathogenic according to our data. Variant chr19-19516253-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1693.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA13	NM_015965.7	MANE Select	c.15G>C	p.Lys5Asn	missense	Exon 1 of 5	NP_057049.5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA13	ENST00000507754.9	TSL:1 MANE Select	c.15G>C	p.Lys5Asn	missense	Exon 1 of 5	ENSP00000423673.1	Q9P0J0-1
	ENSG00000258674	ENST00000555938.1	TSL:2	c.15G>C	p.Lys5Asn	missense	Exon 1 of 7	ENSP00000452549.1	E7ENQ6
	NDUFA13	ENST00000911745.1		c.15G>C	p.Lys5Asn	missense	Exon 1 of 6	ENSP00000581804.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Hurthle cell carcinoma of thyroid (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.9
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.016	D
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.63
MutPred		0.47		Loss of methylation at K5 (P = 0.0036)
MVP		0.96
MPC		0.50
ClinPred		0.99	D
GERP RS		5.3
PromoterAI		-0.0082	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.72
Mutation Taster		=0/100	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: rs137852869; hg19: chr19-19627062; COSMIC: COSV99389320; COSMIC: COSV99389320;