rs1348957889

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. 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 (★).

• 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: Likely_pathogenic. The variant received 8 ACMG points.

• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA11	NM_175614.5	c.97+5G>A		splice_region_variant, intron_variant	Intron 1 of 3	ENST00000308961.5	NP_783313.1
NDUFA11	NM_001193375.3	c.97+5G>A		splice_region_variant, intron_variant	Intron 1 of 3		NP_001180304.1
NDUFA11	NR_034166.3	n.179+5G>A		splice_region_variant, intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA11	ENST00000308961.5	c.97+5G>A		splice_region_variant, intron_variant	Intron 1 of 3	1	NM_175614.5	ENSP00000311740.4
ENSG00000267740	ENST00000585661.1	c.91+5G>A		splice_region_variant, intron_variant	Intron 1 of 3	2		ENSP00000467210.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Mar 21, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97+5 G>A splice site variant in the NDUFA11 gene has been previously reported in association with mitochondrial complex I deficiency in several unrelated individuals who were homozygous for c.97+5 G>A (Berger et al., 2008). This pathogenic variant reduces the quality of the splice donor site in intron 1, and results in abnormal gene splicing (Berger et al., 2008). Therefore, we interpret c.97+5 G>A to be a pathogenic variant. -

Mitochondrial complex I deficiency, nuclear type 14 Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

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;