X-119871908-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.411

Variant links:

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 links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 193286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 91 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NDUFA1	NM_004541.4 link	c.-4A>G		5_prime_UTR_variant	Exon 1 of 3	ENST00000371437.5	NP_004532.1	O15239Q6IBB5
RNF113A	NM_006978.3 link	c.-295T>C		upstream_gene_variant		ENST00000371442.4	NP_008909.1	O15541

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NDUFA1	ENST00000371437 link	c.-4A>G		5_prime_UTR_variant	Exon 1 of 3	1	NM_004541.4	ENSP00000360492.4		O15239
RNF113A	ENST00000371442.4 link	c.-295T>C		upstream_gene_variant		6	NM_006978.3	ENSP00000360497.2		O15541

Frequencies

GnomAD3 genomes

AF:

0.00244

AC:

277

AN:

113332

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

AN XY:

35454

show subpopulations

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

GnomAD3 exomes

AF:

0.000605

AC:

111

AN:

183511

Hom.:

AF XY:

0.000589

AC XY:

AN XY:

67945

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000224

AC XY:

AN XY:

361524

show subpopulations

Gnomad4 AFR exome

AF:

0.00925

Gnomad4 AMR exome

AF:

0.000341

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.000739

GnomAD4 genome

AF:

0.00244

AC:

277

AN:

113383

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

AN XY:

35515

show subpopulations

Gnomad4 AFR

AF:

0.00839

Gnomad4 AMR

AF:

0.000830

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000375

Gnomad4 OTH

AF:

0.00194

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00286

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Apr 25, 2016

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. -

Feb 19, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 23, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided

Benign:1

Mar 05, 2019

Athena Diagnostics

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

-0.60

CADD

Benign

4.3

DANN

Benign

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over