chrX-119871933-G-C

Variant names:

• chrX-119871933-G-C
• rs104894884
• NM_004541.4:c.22G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004541.4(NDUFA1):​c.22G>C​(p.Gly8Arg) variant causes a missense change. 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: 25)
• Consequence: NDUFA1 NM_004541.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.29
• Publications: 15 publications found

Genes affected

NDUFA1 (HGNC:7683): (NADH:ubiquinone oxidoreductase subunit A1) The human NDUFA1 gene codes for an essential component of complex I of the respiratory chain, which transfers electrons from NADH to ubiquinone. It has been noted that the N-terminal hydrophobic domain has the potential to be folded into an alpha-helix spanning the inner mitochondrial membrane with a C-terminal hydrophilic domain interacting with globular subunits of complex I. The highly conserved two-domain structure suggests that this feature is critical for the protein function and might act as an anchor for the NADH:ubiquinone oxidoreductase complex at the inner mitochondrial membrane. However, the NDUFA1 peptide is one of about 31 components of the "hydrophobic protein" (HP) fraction of complex I which is involved in proton translocation. Thus the NDUFA1 peptide may also participate in that function. [provided by RefSeq, Jul 2008]

ENSG00000297015 (HGNC:):

RNF113A (HGNC:12974): (ring finger protein 113A) This intronless gene encodes a protein which contains a C3H1-type zinc finger domain and a C3HC4 Ring-type (Really Interesting New Gene-type) zinc finger domain. The Ring-type zinc finger domain is identified in various tumor suppressors, DNA repair genes and cytokine receptor-associated molecules, and is probably involved in mediating protein-protein interactions. [provided by RefSeq, May 2010]

RNF113A Gene-Disease associations (from GenCC):

• trichothiodystrophy 5, nonphotosensitive

  Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Genomics England PanelApp, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-119871933-G-C is Pathogenic according to our data. Variant chrX-119871933-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11648.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004541.4. 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
	NDUFA1	NM_004541.4	MANE Select	c.22G>C	p.Gly8Arg	missense	Exon 1 of 3	NP_004532.1	O15239
	RNF113A	NM_006978.3	MANE Select	c.-320C>G		upstream_gene	N/A	NP_008909.1	O15541

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA1	ENST00000371437.5	TSL:1 MANE Select	c.22G>C	p.Gly8Arg	missense	Exon 1 of 3	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.22G>C	p.Gly8Arg	missense	Exon 1 of 3	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.22G>C	p.Gly8Arg	missense	Exon 1 of 2	ENSP00000521913.1

Frequencies

GnomAD3 genomes Cov.: 25

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 25

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Mitochondrial complex I deficiency, nuclear type 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.28	D
PhyloP100		6.3
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.76
Sift	Benign	0.13	T
Sift4G	Benign	0.15	T
Polyphen		1.0	D
Vest4		0.81
MutPred		0.78		Gain of solvent accessibility (P = 0.0037)
MVP		0.94
MPC		2.1
ClinPred		0.99	D
GERP RS		5.5
PromoterAI		0.015	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.9
Varity_R		0.84
gMVP		0.99
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs104894884; hg19: chrX-119005896;