X-119871879-A-C

Variant names:

• chrX-119871879-A-C
• rs762694685
• NM_004541.4:c.-33A>C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_004541.4(NDUFA1):​c.-33A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,190,002 control chromosomes in the GnomAD database, including 1 homozygotes. There are 71 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., 8 hem., cov: 24)
  • Exomes 𝑓: 0.00018 (1 hom. 63 hem.)
• Consequence: NDUFA1 NM_004541.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.884

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]

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant X-119871879-A-C is Benign according to our data. Variant chrX-119871879-A-C is described in ClinVar as [Benign]. Clinvar id is 378240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA1	NM_004541.4	c.-33A>C		5_prime_UTR_variant	Exon 1 of 3	ENST00000371437.5	NP_004532.1
RNF113A	NM_006978.3	c.-266T>G		upstream_gene_variant		ENST00000371442.4	NP_008909.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA1	ENST00000371437	c.-33A>C		5_prime_UTR_variant	Exon 1 of 3	1	NM_004541.4	ENSP00000360492.4
RNF113A	ENST00000371442.4	c.-266T>G		upstream_gene_variant		6	NM_006978.3	ENSP00000360497.2

Frequencies

GnomAD3 genomes AF: 0.000203 AC: 23 AN: 113339 Hom.: 0 Cov.: 24 AF XY: 0.000225 AC XY: 8 AN XY: 35485

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000647

Gnomad ASJ AF: 0.000376

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000353

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.000225

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000333 AC: 61 AN: 183453 Hom.: 0 AF XY: 0.000309 AC XY: 21 AN XY: 67889

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000875

Gnomad ASJ exome AF: 0.000134

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00110

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000147

Gnomad OTH exome AF: 0.000662

GnomAD4 exome AF: 0.000176 AC: 189 AN: 1076611 Hom.: 1 Cov.: 28 AF XY: 0.000183 AC XY: 63 AN XY: 344389

Gnomad4 AFR exome AF: 0.0000770

Gnomad4 AMR exome AF: 0.000824

Gnomad4 ASJ exome AF: 0.0000519

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000634

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000912

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000203 AC: 23 AN: 113391 Hom.: 0 Cov.: 24 AF XY: 0.000225 AC XY: 8 AN XY: 35547

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000646

Gnomad4 ASJ AF: 0.000376

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000354

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000225

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000217 Hom.: 0

Bravo AF: 0.000227

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Apr 09, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.3
DANN	Benign	0.53
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs762694685; hg19: chrX-119005842;