19-35742636-A-G

Variant names:

• chr19-35742636-A-G
• rs781687332
• ENST00000292879.9:c.571T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001040425.3(U2AF1L4):​c.*83T>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 0.0000167 in 1,613,664 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: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: U2AF1L4 NM_001040425.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0850
• Publications: 0 publications found

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]

ENSG00000267120 (HGNC:):

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

ACMG classification

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=0.04857704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
U2AF1L4	NM_001040425.3	c.*83T>C		3_prime_UTR_variant	Exon 6 of 6	ENST00000378975.8	NP_001035515.1
IGFLR1	NM_024660.4	c.-284T>C		upstream_gene_variant		ENST00000246532.6	NP_078936.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
U2AF1L4	ENST00000378975.8	c.*83T>C		3_prime_UTR_variant	Exon 6 of 6	1	NM_001040425.3	ENSP00000368258.2
ENSG00000267120	ENST00000589807.1	n.*223-17T>C		intron_variant	Intron 6 of 10	2		ENSP00000472696.1
IGFLR1	ENST00000246532.6	c.-284T>C		upstream_gene_variant		1	NM_024660.4	ENSP00000246532.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250778 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

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: 0.0000171 AC: 25 AN: 1461472 Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.0000224 AC: 1 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53080

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

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.571T>C (p.C191R) 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 571, causing the cysteine (C) at amino acid position 191 to be replaced by an arginine (R). 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	-0.31	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	8.6
DANN	Benign	0.53
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0021	T
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.98	T
PhyloP100		-0.085
PrimateAI	Benign	0.24	T
PROVEAN	Benign	1.8	N
REVEL	Benign	0.027
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.0	B
Vest4		0.12
MutPred		0.39		Gain of phosphorylation at S188 (P = 0.1096);
MVP		0.048
MPC		0.51
ClinPred		0.40	T
GERP RS		-1.7
PromoterAI		-0.036	Neutral
gMVP		0.11
Mutation Taster		=98/2	polymorphism

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: rs781687332; hg19: chr19-36233537;