NM_032830.3:c.418A>G

Variant names:

• chr16-69137867-A-G
• rs1962851495
• NM_032830.3:c.418A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032830.3(UTP4):​c.418A>G​(p.Asn140Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,458,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: UTP4 NM_032830.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.61
• Publications: 0 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3852519).

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.418A>G	p.Asn140Asp	missense	Exon 4 of 17	NP_116219.2	Q969X6-1
	UTP4	NM_001318391.2		c.169A>G	p.Asn57Asp	missense	Exon 4 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.418A>G	p.Asn140Asp	missense	Exon 4 of 17	ENSP00000327179.7	Q969X6-1
	UTP4	ENST00000562237.5	TSL:1	c.460A>G	p.Asn154Asp	missense	Exon 4 of 17	ENSP00000456709.1	H3BSH7
	UTP4	ENST00000960037.1		c.418A>G	p.Asn140Asp	missense	Exon 4 of 17	ENSP00000630096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458830 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725996

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

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

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1109262

Other (OTH) AF: 0.00 AC: 0 AN: 60300

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary North American Indian childhood cirrhosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.087	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.39	T
MetaSVM	Benign	-0.96	T
PhyloP100		6.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.14
Sift	Benign	0.058	T
Sift4G	Uncertain	0.043	D
Polyphen		0.69	P
Vest4		0.34
MutPred		0.54		Gain of ubiquitination at K145 (P = 0.038)
MVP		0.72
MPC		0.62
ClinPred		0.88	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.21
Mutation Taster		=60/40	polymorphism

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: rs1962851495; hg19: chr16-69171770;