chrX-47211069-A-C

Variant names:

• chrX-47211069-A-C
• rs143044923
• NM_003334.4:c.2308A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003334.4(UBA1):​c.2308A>C​(p.Asn770His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,209,932 control chromosomes in the GnomAD database, including 9 homozygotes. There are 401 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N770S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0063 (2 hom., 204 hem., cov: 23)
  • Exomes 𝑓: 0.00068 (7 hom. 197 hem.)
• Consequence: UBA1 NM_003334.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.33
• Publications: 2 publications found

Genes affected

UBA1 (HGNC:12469): (ubiquitin like modifier activating enzyme 1) The protein encoded by this gene catalyzes the first step in ubiquitin conjugation to mark cellular proteins for degradation. This gene complements an X-linked mouse temperature-sensitive defect in DNA synthesis, and thus may function in DNA repair. It is part of a gene cluster on chromosome Xp11.23. Alternatively spliced transcript variants that encode the same protein have been described. [provided by RefSeq, Jul 2008]

UBA1 Gene-Disease associations (from GenCC):

• infantile-onset X-linked spinal muscular atrophy

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• inflammatory disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Ambry Genetics

LOC105373194 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012077421).
• BP6: Variant X-47211069-A-C is Benign according to our data. Variant chrX-47211069-A-C is described in ClinVar as Benign. ClinVar VariationId is 368343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00626 (700/111842) while in subpopulation AFR AF = 0.0218 (672/30762). AF 95% confidence interval is 0.0205. There are 2 homozygotes in GnomAd4. There are 204 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003334.4. 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
	UBA1	NM_003334.4	MANE Select	c.2308A>C	p.Asn770His	missense	Exon 20 of 26	NP_003325.2
	UBA1	NM_001440807.1		c.2350A>C	p.Asn784His	missense	Exon 21 of 27	NP_001427736.1
	UBA1	NM_001440809.1		c.2326A>C	p.Asn776His	missense	Exon 21 of 27	NP_001427738.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA1	ENST00000335972.11	TSL:1 MANE Select	c.2308A>C	p.Asn770His	missense	Exon 20 of 26	ENSP00000338413.6	P22314-1
	UBA1	ENST00000377351.8	TSL:1	c.2308A>C	p.Asn770His	missense	Exon 20 of 26	ENSP00000366568.4	P22314-1
	UBA1	ENST00000880189.1		c.2443A>C	p.Asn815His	missense	Exon 21 of 27	ENSP00000550248.1

Frequencies

GnomAD3 genomes AF: 0.00623 AC: 696 AN: 111791 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00227

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: 0.0000188

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00170 AC: 312 AN: 183100 AF XY: 0.00117

Gnomad AFR exome AF: 0.0207

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.000679 AC: 746 AN: 1098090 Hom.: 7 Cov.: 32 AF XY: 0.000542 AC XY: 197 AN XY: 363460

African (AFR) AF: 0.0222 AC: 587 AN: 26403

American (AMR) AF: 0.00125 AC: 44 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.000148 AC: 8 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40360

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4137

European-Non Finnish (NFE) AF: 0.0000249 AC: 21 AN: 842148

Other (OTH) AF: 0.00174 AC: 80 AN: 46094

GnomAD4 genome AF: 0.00626 AC: 700 AN: 111842 Hom.: 2 Cov.: 23 AF XY: 0.00599 AC XY: 204 AN XY: 34030

African (AFR) AF: 0.0218 AC: 672 AN: 30762

American (AMR) AF: 0.00226 AC: 24 AN: 10598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2701

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53092

Other (OTH) AF: 0.00199 AC: 3 AN: 1508

Alfa AF: 0.00223 Hom.: 120

Bravo AF: 0.00722

ESP6500AA AF: 0.0209 AC: 80

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00195 AC: 237

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Infantile-onset X-linked spinal muscular atrophy (2)
-	-	1	UBA1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		3.3
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.61
Sift	Benign	0.034	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.33
MVP		0.90
MPC		2.1
ClinPred		0.036	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.86
gMVP		0.93
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs143044923; hg19: chrX-47070468;