chrX-119871908-A-G

Variant names:

• chrX-119871908-A-G
• rs201240353
• NM_004541.4:c.-4A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004541.4(NDUFA1):​c.-4A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000472 in 1,209,385 control chromosomes in the GnomAD database, including 1 homozygotes. There are 172 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., 91 hem., cov: 24)
  • Exomes 𝑓: 0.00027 (1 hom. 81 hem.)
• Consequence: NDUFA1 NM_004541.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.411
• 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]

ENSG00000297015 (HGNC:):

RNF113A (HGNC:12974): (ring finger protein 113A) This intronless gene encodes a protein which contains a C3H1-type zinc finger domain and a C3HC4 Ring-type (Really Interesting New Gene-type) zinc finger domain. The Ring-type zinc finger domain is identified in various tumor suppressors, DNA repair genes and cytokine receptor-associated molecules, and is probably involved in mediating protein-protein interactions. [provided by RefSeq, May 2010]

RNF113A Gene-Disease associations (from GenCC):

• trichothiodystrophy 5, nonphotosensitive

  Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Genomics England PanelApp, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• trichothiodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-119871908-A-G is Benign according to our data. Variant chrX-119871908-A-G is described in ClinVar as Benign. ClinVar VariationId is 193286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 91 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.-4A>G		5_prime_UTR	Exon 1 of 3	NP_004532.1	O15239
	RNF113A	NM_006978.3	MANE Select	c.-295T>C		upstream_gene	N/A	NP_008909.1	O15541

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NDUFA1	ENST00000371437.5	TSL:1 MANE Select	c.-4A>G		5_prime_UTR	Exon 1 of 3	ENSP00000360492.4	O15239
	NDUFA1	ENST00000927464.1		c.-4A>G		5_prime_UTR	Exon 1 of 3	ENSP00000597523.1
	NDUFA1	ENST00000851854.1		c.-4A>G		5_prime_UTR	Exon 1 of 2	ENSP00000521913.1

Frequencies

GnomAD3 genomes AF: 0.00244 AC: 277 AN: 113332 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00841

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000831

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00197

GnomAD2 exomes AF: 0.000605 AC: 111 AN: 183511 AF XY: 0.000589

Gnomad AFR exome AF: 0.00798

Gnomad AMR exome AF: 0.000219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000268 AC: 294 AN: 1096002 Hom.: 1 Cov.: 30 AF XY: 0.000224 AC XY: 81 AN XY: 361524

African (AFR) AF: 0.00925 AC: 244 AN: 26367

American (AMR) AF: 0.000341 AC: 12 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19362

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54088

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4132

European-Non Finnish (NFE) AF: 0.00000238 AC: 2 AN: 840079

Other (OTH) AF: 0.000739 AC: 34 AN: 46039

GnomAD4 genome AF: 0.00244 AC: 277 AN: 113383 Hom.: 0 Cov.: 24 AF XY: 0.00256 AC XY: 91 AN XY: 35515

African (AFR) AF: 0.00839 AC: 263 AN: 31350

American (AMR) AF: 0.000830 AC: 9 AN: 10838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2805

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6329

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000375 AC: 2 AN: 53375

Other (OTH) AF: 0.00194 AC: 3 AN: 1543

Alfa AF: 0.00135 Hom.: 10

Bravo AF: 0.00286

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.3
DANN	Benign	0.85
PhyloP100		-0.41
PromoterAI		-0.040	Neutral
Mutation Taster		=300/0	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: rs201240353; hg19: chrX-119005871;