rs3742290

Variant names:

• chr13-52029105-A-G
• rs3742290
• NM_021645.6:c.301A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_021645.6(UTP14C):​c.301A>G​(p.Thr101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,614,132 control chromosomes in the GnomAD database, including 11,325 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (811 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10514 hom.)
• Consequence: UTP14C NM_021645.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.590
• Publications: 42 publications found

Genes affected

UTP14C (HGNC:20321): (UTP14C small subunit processome component) Predicted to be involved in several processes, including meiotic cell cycle; rRNA processing; and spermatogenesis. Located in cytosol and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ALG11 (HGNC:32456): (ALG11 alpha-1,2-mannosyltransferase) This gene encodes a GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase which is localized to the cytosolic side of the endoplasmic reticulum (ER) and catalyzes the transfer of the fourth and fifth mannose residue from GDP-mannose (GDP-Man) to Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol resulting in the production of Man5GlcNAc2-PP-dolichol. Mutations in this gene are associated with congenital disorder of glycosylation type Ip (CDGIP). This gene overlaps but is distinct from the UTP14, U3 small nucleolar ribonucleoprotein, homolog C (yeast) gene. A pseudogene of the GDP-Man:Man3GlcNAc2-PP-dolichol-alpha1,2-mannosyltransferase has been identified on chromosome 19. [provided by RefSeq, Aug 2010]

ALG11 Gene-Disease associations (from GenCC):

• ALG11-congenital disorder of glycosylation

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, ClinGen, Ambry Genetics, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.001627624).
• BP6: Variant 13-52029105-A-G is Benign according to our data. Variant chr13-52029105-A-G is described in CliVar as Benign. Clinvar id is 312423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-52029105-A-G is described in CliVar as Benign. Clinvar id is 312423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-52029105-A-G is described in CliVar as Benign. Clinvar id is 312423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.121 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UTP14C	NM_021645.6	c.301A>G	p.Thr101Ala	missense_variant	Exon 2 of 2	ENST00000521776.2	NP_067677.4
ALG11	NM_001004127.3	c.*515A>G		3_prime_UTR_variant	Exon 4 of 4	ENST00000521508.2	NP_001004127.2
ALG11	NR_036571.3	n.852A>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UTP14C	ENST00000521776.2	c.301A>G	p.Thr101Ala	missense_variant	Exon 2 of 2	1	NM_021645.6	ENSP00000428619.1
ALG11	ENST00000521508.2	c.*515A>G		3_prime_UTR_variant	Exon 4 of 4	1	NM_001004127.3	ENSP00000430236.1

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15709 AN: 152136 Hom.: 811 Cov.: 32

Gnomad AFR AF: 0.0613

Gnomad AMI AF: 0.173

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.0621

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.122

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.123

Gnomad OTH AF: 0.116

GnomAD2 exomes AF: 0.111 AC: 27943 AN: 251436 AF XY: 0.112

Gnomad AFR exome AF: 0.0615

Gnomad AMR exome AF: 0.117

Gnomad ASJ exome AF: 0.117

Gnomad EAS exome AF: 0.0693

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.128

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.117 AC: 170743 AN: 1461878 Hom.: 10514 Cov.: 106 AF XY: 0.116 AC XY: 84512 AN XY: 727244

African (AFR) AF: 0.0600 AC: 2009 AN: 33480

American (AMR) AF: 0.116 AC: 5193 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 3175 AN: 26136

East Asian (EAS) AF: 0.0518 AC: 2055 AN: 39700

South Asian (SAS) AF: 0.0890 AC: 7676 AN: 86258

European-Finnish (FIN) AF: 0.118 AC: 6297 AN: 53418

Middle Eastern (MID) AF: 0.158 AC: 911 AN: 5768

European-Non Finnish (NFE) AF: 0.123 AC: 136527 AN: 1112000

Other (OTH) AF: 0.114 AC: 6900 AN: 60396

GnomAD4 genome AF: 0.103 AC: 15719 AN: 152254 Hom.: 811 Cov.: 32 AF XY: 0.103 AC XY: 7653 AN XY: 74432

African (AFR) AF: 0.0613 AC: 2548 AN: 41554

American (AMR) AF: 0.123 AC: 1883 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3472

East Asian (EAS) AF: 0.0622 AC: 323 AN: 5190

South Asian (SAS) AF: 0.0853 AC: 412 AN: 4828

European-Finnish (FIN) AF: 0.122 AC: 1297 AN: 10592

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.123 AC: 8387 AN: 68002

Other (OTH) AF: 0.114 AC: 242 AN: 2116

Alfa AF: 0.116 Hom.: 3466

Bravo AF: 0.104

TwinsUK AF: 0.127 AC: 471

ALSPAC AF: 0.117 AC: 451

ESP6500AA AF: 0.0631 AC: 278

ESP6500EA AF: 0.119 AC: 1023

ExAC AF: 0.112 AC: 13594

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.128

EpiControl AF: 0.131

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 04, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ALG11-congenital disorder of glycosylation Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.35
DANN	Benign	0.82
DEOGEN2	Benign	0.0024	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.020	N
PhyloP100		-0.59
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.011
Sift	Benign	0.79	T
Sift4G	Benign	0.83	T
Polyphen		0.0040	B
Vest4		0.024
MPC		0.078
ClinPred		0.0032	T
GERP RS		0.15
Varity_R		0.028
gMVP		0.050
Mutation Taster		=98/2	polymorphism (auto)

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: rs3742290; hg19: chr13-52603241; COSMIC: COSV73000566; COSMIC: COSV73000566;