rs1367830417

Variant names:

• chrX-119871927-C-T
• rs1367830417
• NM_004541.4:c.16C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP3 BS2

The NM_004541.4(NDUFA1):​c.16C>T​(p.Leu6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,097,771 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: NDUFA1 NM_004541.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 3.45
• Publications: 1 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_benign. The variant received -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.77
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL,AR gene

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.16C>T	p.Leu6Phe	missense	Exon 1 of 3	NP_004532.1	O15239
	RNF113A	NM_006978.3	MANE Select	c.-314G>A		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.16C>T	p.Leu6Phe	missense	Exon 1 of 3	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.16C>T	p.Leu6Phe	missense	Exon 1 of 3	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.16C>T	p.Leu6Phe	missense	Exon 1 of 2	ENSP00000521913.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1097771 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 2 AN XY: 363131

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841691

Other (OTH) AF: 0.00 AC: 0 AN: 46080

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	NDUFA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.063	D
PhyloP100		3.5
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.68
Sift	Benign	0.088	T
Sift4G	Benign	0.079	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.67		Gain of sheet (P = 0.1945)
MVP		0.83
MPC		1.9
ClinPred		0.99	D
GERP RS		3.6
PromoterAI		-0.015	Neutral
Varity_R		0.70
gMVP		0.99
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1367830417; hg19: chrX-119005890; COSMIC: COSV65097991; COSMIC: COSV65097991;