Genetic Variant U2AF1L4:p.Ser188Pro (chr19-35742645-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001040425.3(U2AF1L4):c.*74T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 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: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

U2AF1L4
NM_001040425.3 3_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.465

Publications

0 publications found

Variant links:

Genes affected

U2AF1L4 (HGNC:23020): (U2 small nuclear RNA auxiliary factor 1 like 4) Predicted to enable pre-mRNA 3'-splice site binding activity. Predicted to be involved in mRNA splicing, via spliceosome. Predicted to be located in nucleoplasm. Predicted to be part of U2AF complex and spliceosomal complex. [provided by Alliance of Genome Resources, Apr 2022]

U2AF1L4 links:

ENSG00000267120 (HGNC:):

ENSG00000267120 links:

IGFLR1 (HGNC:23620): (IGF like family receptor 1) Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

IGFLR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.063583314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1L4	NM_001040425.3 link	c.*74T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000378975.8	NP_001035515.1	Q8WU68-3
IGFLR1	NM_024660.4 link	c.-293T>C		upstream_gene_variant		ENST00000246532.6	NP_078936.1	Q9H665-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
U2AF1L4	ENST00000378975.8 link	c.*74T>C	3_prime_UTR_variant	Exon 6 of 6	1	NM_001040425.3	ENSP00000368258.2	Q8WU68-3
ENSG00000267120	ENST00000589807.1 link	n.*223-26T>C	intron_variant	Intron 6 of 10	2		ENSP00000472696.1	M0R2N4
IGFLR1	ENST00000246532.6 link	c.-293T>C	upstream_gene_variant		1	NM_024660.4	ENSP00000246532.1	Q9H665-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461392

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726950

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33452

American (AMR)

AF:

0.00

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53062

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111948

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.562T>C (p.S188P) alteration is located in exon 6 (coding exon 6) of the U2AF1L4 gene. This alteration results from a T to C substitution at nucleotide position 562, causing the serine (S) at amino acid position 188 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.73

Eigen

Benign

-0.93

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.069

LIST_S2

Benign

0.28

M_CAP

Benign

0.0031

MetaRNN

Benign

0.064

MetaSVM

Benign

-1.0

PhyloP100

0.47

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.79

REVEL

Benign

0.034

Sift

Benign

0.17

Sift4G

Benign

0.16

Polyphen

0.0010

Vest4

0.16

MutPred

0.17

Gain of glycosylation at S188 (P = 0.0148);

MVP

0.048

MPC

0.36

ClinPred

0.080

GERP RS

-0.51

PromoterAI

0.0056

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.15

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-35742645-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over