NM_001040425.3:c.371G>A

Variant names:

• chr19-35743899-C-T
• rs780666454
• NM_001040425.3:c.371G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001040425.3(U2AF1L4):​c.371G>A​(p.Cys124Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,540 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C124S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: U2AF1L4 NM_001040425.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64
• Publications: 1 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981

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.371G>A	p.Cys124Tyr	missense	Exon 5 of 6	NP_001035515.1	Q8WU68-3
	U2AF1L4	NM_144987.4		c.313G>A	p.Val105Ile	missense	Exon 5 of 6	NP_659424.2	Q8WU68-2
	U2AF1L4	NM_001369824.2		c.313G>A	p.Val105Ile	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.371G>A	p.Cys124Tyr	missense	Exon 5 of 6	ENSP00000368258.2	Q8WU68-3
	U2AF1L4	ENST00000292879.9	TSL:1	c.313G>A	p.Val105Ile	missense	Exon 5 of 6	ENSP00000292879.4	Q8WU68-2
	U2AF1L4	ENST00000587987.5	TSL:1	n.*339G>A		non_coding_transcript_exon	Exon 6 of 8	ENSP00000465170.1	K7EJH3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461436 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726960

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86218

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53374

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111754

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41376

American (AMR) AF: 0.00 AC: 0 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2086

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.45	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.051
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Benign	-0.99	T
PhyloP100		5.6
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.81		Loss of catalytic residue at C163 (P = 0.0326)
MVP		0.50
ClinPred		0.92	D
GERP RS		4.4
Varity_R		0.76
Mutation Taster		=58/42	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: rs780666454; hg19: chr19-36234800;