21-43104346-G-A

Variant names:

• chr21-43104346-G-A
• rs371769427
• NM_006758.3:c.101C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP2 PP3_Moderate

The NM_006758.3(U2AF1):​c.101C>T​(p.Ser34Phe) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: U2AF1 NM_006758.3 missense
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 9.05
• Publications: 330 publications found

Genes affected

U2AF1 (HGNC:12453): (U2 small nuclear RNA auxiliary factor 1) This gene belongs to the splicing factor SR family of genes. U2 auxiliary factor, comprising a large and a small subunit, is a non-snRNP protein required for the binding of U2 snRNP to the pre-mRNA branch site. This gene encodes the small subunit which plays a critical role in both constitutive and enhancer-dependent RNA splicing by directly mediating interactions between the large subunit and proteins bound to the enhancers. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 3.8478 (above the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09).
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.875

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006758.3. 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
	U2AF1	NM_006758.3	MANE Select	c.101C>T	p.Ser34Phe	missense	Exon 2 of 8	NP_006749.1	Q01081-1
	U2AF1	NM_001025203.1		c.101C>T	p.Ser34Phe	missense	Exon 2 of 8	NP_001020374.1	Q01081-2
	U2AF1	NM_001025204.2		c.-186C>T		5_prime_UTR	Exon 2 of 9	NP_001020375.1	Q01081-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	U2AF1	ENST00000291552.9	TSL:1 MANE Select	c.101C>T	p.Ser34Phe	missense	Exon 2 of 8	ENSP00000291552.4	Q01081-1
	U2AF1	ENST00000380276.6	TSL:1	c.101C>T	p.Ser34Phe	missense	Exon 2 of 8	ENSP00000369629.2	Q01081-2
	U2AF1	ENST00000459639.5	TSL:1	c.-119C>T		5_prime_UTR	Exon 1 of 7	ENSP00000418705.1	Q01081-4

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 986 Hom.: 0 Cov.: 0

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 249860 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 17950 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 9092

African (AFR) AF: 0.00 AC: 0 AN: 558

American (AMR) AF: 0.00 AC: 0 AN: 324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 796

East Asian (EAS) AF: 0.00 AC: 0 AN: 2190

South Asian (SAS) AF: 0.00 AC: 0 AN: 480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 838

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 72

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 11486

Other (OTH) AF: 0.00 AC: 0 AN: 1206

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 986 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 500

African (AFR) AF: 0.00 AC: 0 AN: 146

American (AMR) AF: 0.00 AC: 0 AN: 134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 186

South Asian (SAS) AF: 0.00 AC: 0 AN: 102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 10

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 348

Other (OTH) AF: 0.00 AC: 0 AN: 26

Alfa AF: 0.000103 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.082	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		9.1
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.70
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MVP		0.77
MPC		2.7
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.92
gMVP		0.99
Mutation Taster		=151/149	disease causing (ClinVar)

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: rs371769427; hg19: chr21-44524456; COSMIC: COSV52341059; COSMIC: COSV52341059;