X-119873266-T-C

Variant names:

• chrX-119873266-T-C
• rs1800824
• NM_004541.4:c.103-38T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004541.4(NDUFA1):​c.103-38T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000401 in 998,060 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.0000040 (0 hom. 0 hem.)
• Consequence: NDUFA1 NM_004541.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.556
• Publications: 4 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]

NDUFA1 Gene-Disease associations (from GenCC):

• mitochondrial complex I deficiency, nuclear type 12

  Inheritance: XL, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• Leigh syndrome

  Inheritance: XL Classification: MODERATE Submitted by: ClinGen
• mitochondrial complex I deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000297015 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA1	NM_004541.4	c.103-38T>C		intron_variant	Intron 1 of 2	ENST00000371437.5	NP_004532.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA1	ENST00000371437.5	c.103-38T>C		intron_variant	Intron 1 of 2	1	NM_004541.4	ENSP00000360492.4
ENSG00000297015	ENST00000744274.1	n.261+9565A>G		intron_variant	Intron 2 of 2
ENSG00000297015	ENST00000744275.1	n.163-19547A>G		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.00000401 AC: 4 AN: 998060 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 296666

African (AFR) AF: 0.00 AC: 0 AN: 24499

American (AMR) AF: 0.00 AC: 0 AN: 35079

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18753

East Asian (EAS) AF: 0.00 AC: 0 AN: 29706

South Asian (SAS) AF: 0.00 AC: 0 AN: 51974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40389

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3921

European-Non Finnish (NFE) AF: 0.00000533 AC: 4 AN: 751095

Other (OTH) AF: 0.00 AC: 0 AN: 42644

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 948

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.2
DANN	Benign	0.67
PhyloP100		-0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800824; hg19: chrX-119007229;