rs1348957889

Variant names:

• chr19-5903607-C-T
• rs1348957889
• NM_175614.5:c.97+5G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PM2 PP3_Strong PP5_Moderate

The NM_175614.5(NDUFA11):​c.97+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). ClinVar reports functional evidence for this variant: "SCV000617289: This pathogenic variant reduces the quality of the splice donor site in intron 1, and results in abnormal gene splicing (Berger et al., 2008).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: NDUFA11 NM_175614.5 splice_region, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.19
• Publications: 0 publications found

Genes affected

NDUFA11 (HGNC:20371): (NADH:ubiquinone oxidoreductase subunit A11) This gene encodes a subunit of the membrane-bound mitochondrial complex I. Complex I is composed of numerous subunits and functions as the NADH-ubiquinol reductase of the mitochondrial electron transport chain. Mutations in this gene are associated with severe mitochondrial complex I deficiency. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

NDUFA11 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 14

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• mitochondrial disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ENSG00000267740 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000617289: This pathogenic variant reduces the quality of the splice donor site in intron 1, and results in abnormal gene splicing (Berger et al., 2008).
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 19-5903607-C-T is Pathogenic according to our data. Variant chr19-5903607-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 449316.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175614.5. 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
	NDUFA11	NM_175614.5	MANE Select	c.97+5G>A		splice_region intron	N/A	NP_783313.1	Q86Y39-1
	NDUFA11	NM_001193375.3		c.97+5G>A		splice_region intron	N/A	NP_001180304.1	Q86Y39-2
	NDUFA11	NR_034166.3		n.179+5G>A		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA11	ENST00000308961.5	TSL:1 MANE Select	c.97+5G>A		splice_region intron	N/A	ENSP00000311740.4	Q86Y39-1
	ENSG00000267740	ENST00000585661.1	TSL:2	c.91+5G>A		splice_region intron	N/A	ENSP00000467210.1	K7EP35
	NDUFA11	ENST00000418389.7	TSL:2	c.97+5G>A		splice_region intron	N/A	ENSP00000389160.1	Q86Y39-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 14 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Benign	0.80
PhyloP100		2.2
PromoterAI		-0.46	Neutral
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.47		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: -43
DS_DL_spliceai		0.47		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1348957889; hg19: chr19-5903618;