NM_004541.4:c.103-244T>A

Variant names:

• chrX-119873060-T-A
• rs2428220
• NM_004541.4:c.103-244T>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004541.4(NDUFA1):​c.103-244T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.44 (7699 hom., 10474 hem., cov: 18)
• Consequence: NDUFA1 NM_004541.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.89
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-119873060-T-A is Benign according to our data. Variant chrX-119873060-T-A is described in ClinVar as Benign. ClinVar VariationId is 1178983.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.631 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.103-244T>A		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.103-244T>A		intron	N/A	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.103-244T>A		intron	N/A	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.102+1047T>A		intron	N/A	ENSP00000521913.1

Frequencies

GnomAD3 genomes AF: 0.436 AC: 43789 AN: 100414 Hom.: 7704 Cov.: 18

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.556

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.654

Gnomad SAS AF: 0.409

Gnomad FIN AF: 0.365

Gnomad MID AF: 0.422

Gnomad NFE AF: 0.355

Gnomad OTH AF: 0.457

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

GnomAD4 genome AF: 0.436 AC: 43797 AN: 100426 Hom.: 7699 Cov.: 18 AF XY: 0.414 AC XY: 10474 AN XY: 25272

African (AFR) AF: 0.541 AC: 14542 AN: 26899

American (AMR) AF: 0.556 AC: 5063 AN: 9111

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 915 AN: 2510

East Asian (EAS) AF: 0.654 AC: 2113 AN: 3232

South Asian (SAS) AF: 0.408 AC: 899 AN: 2202

European-Finnish (FIN) AF: 0.365 AC: 1461 AN: 4008

Middle Eastern (MID) AF: 0.409 AC: 83 AN: 203

European-Non Finnish (NFE) AF: 0.355 AC: 17850 AN: 50249

Other (OTH) AF: 0.452 AC: 626 AN: 1386

Alfa AF: 0.392 Hom.: 2166

ClinVar

ClinVar submissions

Significance: 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
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.59
DANN	Benign	0.62
PhyloP100		-4.9
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: rs2428220; hg19: chrX-119007023;