X-119873028-A-G

Variant names:

• chrX-119873028-A-G
• rs5910697
• NM_004541.4:c.103-276A>G

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.103-276A>G 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 0.087 (405 hom., 2366 hem., cov: 20)
• Consequence: NDUFA1 NM_004541.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.192
• 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=-1.01).
• BP6: Variant X-119873028-A-G is Benign according to our data. Variant chrX-119873028-A-G is described in ClinVar as Benign. ClinVar VariationId is 1237407.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.149 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.103-276A>G		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.103-276A>G		intron	N/A	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.103-276A>G		intron	N/A	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.102+1015A>G		intron	N/A	ENSP00000521913.1

Frequencies

GnomAD3 genomes AF: 0.0866 AC: 9220 AN: 106429 Hom.: 403 Cov.: 20

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00593

Gnomad AMR AF: 0.0721

Gnomad ASJ AF: 0.0537

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.181

Gnomad NFE AF: 0.0554

Gnomad OTH AF: 0.0989

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

GnomAD4 genome AF: 0.0867 AC: 9228 AN: 106450 Hom.: 405 Cov.: 20 AF XY: 0.0806 AC XY: 2366 AN XY: 29350

African (AFR) AF: 0.153 AC: 4427 AN: 28981

American (AMR) AF: 0.0719 AC: 700 AN: 9737

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 140 AN: 2605

East Asian (EAS) AF: 0.154 AC: 526 AN: 3416

South Asian (SAS) AF: 0.102 AC: 242 AN: 2383

European-Finnish (FIN) AF: 0.0254 AC: 128 AN: 5033

Middle Eastern (MID) AF: 0.189 AC: 39 AN: 206

European-Non Finnish (NFE) AF: 0.0554 AC: 2879 AN: 51974

Other (OTH) AF: 0.0993 AC: 143 AN: 1440

Alfa AF: 0.0666 Hom.: 5411

Bravo AF: 0.0964

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	-1.0
CADD	Benign	5.0
DANN	Benign	0.48
PhyloP100		0.19
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: rs5910697; hg19: chrX-119006991;