rs1030203914

Variant names:

• chr16-69133574-A-G
• rs1030203914
• NM_032830.3:c.115A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032830.3(UTP4):​c.115A>G​(p.Thr39Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UTP4 NM_032830.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 1.57
• Publications: 2 publications found

Genes affected

UTP4 (HGNC:1983): (UTP4 small subunit processome component) This gene encodes a WD40-repeat-containing protein that is localized to the nucleolus. Mutation of this gene causes North American Indian childhood cirrhosis, a severe intrahepatic cholestasis that results in transient neonatal jaundice, and progresses to periportal fibrosis and cirrhosis in childhood and adolescence. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

UTP4 Gene-Disease associations (from GenCC):

• hereditary North American Indian childhood cirrhosis

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
• cirrhosis, familial

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14336613).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032830.3. 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
	UTP4	NM_032830.3	MANE Select	c.115A>G	p.Thr39Ala	missense	Exon 2 of 17	NP_116219.2	Q969X6-1
	UTP4	NM_001318391.2		c.-135A>G		5_prime_UTR	Exon 2 of 17	NP_001305320.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UTP4	ENST00000314423.12	TSL:1 MANE Select	c.115A>G	p.Thr39Ala	missense	Exon 2 of 17	ENSP00000327179.7	Q969X6-1
	UTP4	ENST00000562237.5	TSL:1	c.157A>G	p.Thr53Ala	missense	Exon 2 of 17	ENSP00000456709.1	H3BSH7
	UTP4	ENST00000960037.1		c.115A>G	p.Thr39Ala	missense	Exon 2 of 17	ENSP00000630096.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251416 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727228

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	UTP4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.028
FATHMM_MKL	Benign	0.55	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.079
Sift	Benign	0.29	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.17
MutPred		0.38		Loss of methylation at R35 (P = 0.1267)
MVP		0.55
MPC		0.18
ClinPred		0.13	T
GERP RS		3.7
Varity_R		0.079
gMVP		0.42

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

Other links and lift over

dbSNP: rs1030203914; hg19: chr16-69167477; COSMIC: COSV58734562; COSMIC: COSV58734562;