X-119873060-TAA-TA

Variant names:

• chrX-119873060-TA-T
• rs57808963
• NM_004541.4:c.103-235delA

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_004541.4(NDUFA1):​c.103-235delA 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 0.011 (6 hom., 262 hem., cov: 18)
• Consequence: NDUFA1 NM_004541.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.111
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-119873060-TA-T is Benign according to our data. Variant chrX-119873060-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1218563.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 6 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.103-235delA		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.103-243delA		intron	N/A	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.103-243delA		intron	N/A	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.102+1048delA		intron	N/A	ENSP00000521913.1

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1085 AN: 100560 Hom.: 6 Cov.: 18

Gnomad AFR AF: 0.00747

Gnomad AMI AF: 0.00479

Gnomad AMR AF: 0.00812

Gnomad ASJ AF: 0.00279

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0140

Gnomad FIN AF: 0.00571

Gnomad MID AF: 0.0541

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.0183

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

GnomAD4 genome AF: 0.0108 AC: 1086 AN: 100571 Hom.: 6 Cov.: 18 AF XY: 0.0103 AC XY: 262 AN XY: 25333

African (AFR) AF: 0.00750 AC: 202 AN: 26950

American (AMR) AF: 0.00811 AC: 74 AN: 9120

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 7 AN: 2513

East Asian (EAS) AF: 0.00124 AC: 4 AN: 3236

South Asian (SAS) AF: 0.0141 AC: 31 AN: 2205

European-Finnish (FIN) AF: 0.00571 AC: 23 AN: 4026

Middle Eastern (MID) AF: 0.0594 AC: 12 AN: 202

European-Non Finnish (NFE) AF: 0.0140 AC: 705 AN: 50306

Other (OTH) AF: 0.0180 AC: 25 AN: 1387

Alfa AF: 0.00564 Hom.: 42

ClinVar

ClinVar submissions as Germline

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		0.11
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: rs57808963; hg19: chrX-119007023;