X-119873266-T-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004541.4(NDUFA1):​c.103-38T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0662 in 1,108,649 control chromosomes in the GnomAD database, including 2,224 homozygotes. There are 22,893 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.087 (408 hom., 2646 hem., cov: 21)
  • Exomes 𝑓: 0.064 (1816 hom. 20247 hem.)
• Consequence: NDUFA1 NM_004541.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-119873266-T-G is Benign according to our data. Variant chrX-119873266-T-G is described in ClinVar as Benign. ClinVar VariationId is 1248855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0865 AC: 9582 AN: 110805 Hom.: 406 Cov.: 21

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00586

Gnomad AMR AF: 0.0715

Gnomad ASJ AF: 0.0530

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.0943

Gnomad FIN AF: 0.0289

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.0556

Gnomad OTH AF: 0.0941

GnomAD2 exomes AF: 0.0784 AC: 14357 AN: 183064 AF XY: 0.0778

Gnomad AFR exome AF: 0.156

Gnomad AMR exome AF: 0.0723

Gnomad ASJ exome AF: 0.0531

Gnomad EAS exome AF: 0.166

Gnomad FIN exome AF: 0.0322

Gnomad NFE exome AF: 0.0572

Gnomad OTH exome AF: 0.0812

GnomAD4 exome AF: 0.0640 AC: 63827 AN: 997789 Hom.: 1816 Cov.: 19 AF XY: 0.0683 AC XY: 20247 AN XY: 296653

African (AFR) AF: 0.156 AC: 3827 AN: 24481

American (AMR) AF: 0.0713 AC: 2501 AN: 35075

Ashkenazi Jewish (ASJ) AF: 0.0531 AC: 995 AN: 18751

East Asian (EAS) AF: 0.189 AC: 5600 AN: 29699

South Asian (SAS) AF: 0.112 AC: 5828 AN: 51961

European-Finnish (FIN) AF: 0.0343 AC: 1386 AN: 40389

Middle Eastern (MID) AF: 0.139 AC: 545 AN: 3921

European-Non Finnish (NFE) AF: 0.0530 AC: 39795 AN: 750881

Other (OTH) AF: 0.0786 AC: 3350 AN: 42631

GnomAD4 genome AF: 0.0865 AC: 9592 AN: 110860 Hom.: 408 Cov.: 21 AF XY: 0.0800 AC XY: 2646 AN XY: 33088

African (AFR) AF: 0.152 AC: 4623 AN: 30499

American (AMR) AF: 0.0713 AC: 736 AN: 10323

Ashkenazi Jewish (ASJ) AF: 0.0530 AC: 140 AN: 2642

East Asian (EAS) AF: 0.154 AC: 544 AN: 3525

South Asian (SAS) AF: 0.0938 AC: 249 AN: 2655

European-Finnish (FIN) AF: 0.0289 AC: 168 AN: 5817

Middle Eastern (MID) AF: 0.181 AC: 39 AN: 216

European-Non Finnish (NFE) AF: 0.0556 AC: 2947 AN: 52994

Other (OTH) AF: 0.0943 AC: 142 AN: 1506

Alfa AF: 0.0642 Hom.: 948

Bravo AF: 0.0964

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.0
DANN	Benign	0.70
PhyloP100		-0.56
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: rs1800824; hg19: chrX-119007229; COSMIC: COSV65097965; COSMIC: COSV65097965;