19-35743871-C-A

Variant names:

• chr19-35743871-C-A
• rs200068081
• NM_001040425.3:c.399G>T

Variant summary

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

The NM_001040425.3(U2AF1L4):​c.399G>T​(p.Met133Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,482 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M133V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: U2AF1L4 NM_001040425.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.26
• Publications: 2 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:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040425.3. 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
	U2AF1L4	NM_001040425.3	MANE Select	c.399G>T	p.Met133Ile	missense	Exon 5 of 6	NP_001035515.1	Q8WU68-3
	U2AF1L4	NM_144987.4		c.341G>T	p.Cys114Phe	missense	Exon 5 of 6	NP_659424.2	Q8WU68-2
	U2AF1L4	NM_001369824.2		c.341G>T	p.Cys114Phe	missense	Exon 5 of 6	NP_001356753.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF1L4	ENST00000378975.8	TSL:1 MANE Select	c.399G>T	p.Met133Ile	missense	Exon 5 of 6	ENSP00000368258.2	Q8WU68-3
	U2AF1L4	ENST00000292879.9	TSL:1	c.341G>T	p.Cys114Phe	missense	Exon 5 of 6	ENSP00000292879.4	Q8WU68-2
	U2AF1L4	ENST00000587987.5	TSL:1	n.*367G>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000465170.1	K7EJH3

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000967

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: 0.0000160 AC: 4 AN: 250006 AF XY: 0.0000296

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000266

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461440 Hom.: 0 Cov.: 34 AF XY: 0.0000426 AC XY: 31 AN XY: 726982

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

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

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111824

Other (OTH) AF: 0.0000166 AC: 1 AN: 60376

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74244

African (AFR) AF: 0.0000967 AC: 4 AN: 41370

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000545 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.38	T
M_CAP	Benign	0.0071	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.1	T
PhyloP100		7.3
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.90	P
Vest4		0.79
MVP		0.23
MPC		0.36
ClinPred		0.89	D
GERP RS		5.2
Varity_R		0.16
gMVP		0.55
Mutation Taster		=65/35	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: rs200068081; hg19: chr19-36234772;