X-119873045-CTTTTTT-CTTTTTTT

Variant names:

• chrX-119873045-C-CT
• rs373911727
• NM_004541.4:c.103-244dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_004541.4(NDUFA1):​c.103-244dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.020 (18 hom., 313 hem., cov: 20)
• Consequence: NDUFA1 NM_004541.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.970
• Publications: 0 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: AR, XL Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant X-119873045-C-CT is Benign according to our data. Variant chrX-119873045-C-CT is described in ClinVar as Likely_benign. ClinVar VariationId is 1211550.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0678 is higher than 0.05.

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.103-244dupT		intron	N/A	NP_004532.1	O15239

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA1	ENST00000371437.5	TSL:1 MANE Select	c.103-259_103-258insT		intron	N/A	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.103-259_103-258insT		intron	N/A	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.102+1032_102+1033insT		intron	N/A	ENSP00000521913.1

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 1654 AN: 81963 Hom.: 18 Cov.: 20

Gnomad AFR AF: 0.00494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0356

Gnomad ASJ AF: 0.0227

Gnomad EAS AF: 0.0759

Gnomad SAS AF: 0.0355

Gnomad FIN AF: 0.00821

Gnomad MID AF: 0.0460

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0190

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0202 AC: 1655 AN: 81937 Hom.: 18 Cov.: 20 AF XY: 0.0168 AC XY: 313 AN XY: 18655

African (AFR) AF: 0.00493 AC: 105 AN: 21291

American (AMR) AF: 0.0356 AC: 265 AN: 7452

Ashkenazi Jewish (ASJ) AF: 0.0227 AC: 48 AN: 2110

East Asian (EAS) AF: 0.0762 AC: 210 AN: 2755

South Asian (SAS) AF: 0.0360 AC: 63 AN: 1749

European-Finnish (FIN) AF: 0.00821 AC: 24 AN: 2924

Middle Eastern (MID) AF: 0.0327 AC: 5 AN: 153

European-Non Finnish (NFE) AF: 0.0217 AC: 911 AN: 41904

Other (OTH) AF: 0.0225 AC: 24 AN: 1065

Alfa AF: 0.00268 Hom.: 5

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.97
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs373911727; hg19: chrX-119007008;