rs745662721

Variant names:

• chr19-41302850-G-A
• rs745662721
• NM_007040.6:c.1873G>A
• HNRNPUL1 p.Gly625Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_007040.6(HNRNPUL1):c.1873G>A (p.Gly625Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00000349 (AC=5) in the gnomAD database across 1,433,740 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00000134. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: HNRNPUL1 NM_007040.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86
• Publications: 0 publications found

Genes affected

HNRNPUL1 (HGNC:17011): (heterogeneous nuclear ribonucleoprotein U like 1) This gene encodes a nuclear RNA-binding protein of the heterogeneous nuclear ribonucleoprotein (hnRNP) family. This protein binds specifically to adenovirus early-1B-55kDa oncoprotein. It may play an important role in nucleocytoplasmic RNA transport, and its function is modulated by early-1B-55kDa in adenovirus-infected cells. [provided by RefSeq, Mar 2016]

TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TGFB1 Gene-Disease associations (from GenCC):

• Camurati-Engelmann disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Camurati-Engelmann disease type 1

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• inflammatory bowel disease, immunodeficiency, and encephalopathy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000134 — very rare for unknown gene (threshold 0.001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007040.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HNRNPUL1 NM_007040.6	MANE Select	c.1873G>A p.Gly625Ser	missense	Exon 12 of 15	Prot: NP_008971.2
	HNRNPUL1 NM_001439168.1		c.1873G>A p.Gly625Ser	missense	Exon 12 of 15	Prot: NP_001426097.1
	HNRNPUL1 NM_001439167.1		c.1873G>A p.Gly625Ser	missense	Exon 12 of 15	Prot: NP_001426096.1 UniProt:

HNRNPUL1 NM_007040.6

MANE Select

HGVSc / HGVSpc.1873G>Ap.Gly625Ser

Exon rankExon 12 of 15

missense

Prot: NP_008971.2

HNRNPUL1 NM_001439168.1

HGVSc / HGVSpc.1873G>Ap.Gly625Ser

Exon rankExon 12 of 15

missense

Prot: NP_001426097.1

HNRNPUL1 NM_001439167.1

HGVSc / HGVSpc.1873G>Ap.Gly625Ser

Exon rankExon 12 of 15

missense

Prot: NP_001426096.1UniProt: Q9BUJ2-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HNRNPUL1 ENST00000392006.8	TSL:1MANE Select	c.1873G>A p.Gly625Ser	missense	Exon 12 of 15	Prot: ENSP00000375863.2 UniProt:
	HNRNPUL1 ENST00000602130.5	TSL:1	c.1873G>A p.Gly625Ser	missense	Exon 12 of 15	Prot: ENSP00000470687.1 UniProt:
	HNRNPUL1 ENST00000352456.7	TSL:1	c.1573G>A p.Gly525Ser	missense	Exon 12 of 15	Prot: ENSP00000340857.3 UniProt:

HNRNPUL1 ENST00000392006.8

TSL:1MANE Select

HGVSc / HGVSpc.1873G>Ap.Gly625Ser

Exon rankExon 12 of 15

missense

Prot: ENSP00000375863.2UniProt: Q9BUJ2-1

HNRNPUL1 ENST00000602130.5

TSL:1

HGVSc / HGVSpc.1873G>Ap.Gly625Ser

Exon rankExon 12 of 15

missense

Prot: ENSP00000470687.1UniProt: Q9BUJ2-2

HNRNPUL1 ENST00000352456.7

TSL:1

HGVSc / HGVSpc.1573G>Ap.Gly525Ser

Exon rankExon 12 of 15

missense

Prot: ENSP00000340857.3UniProt: A0A0A0MRA5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD2 exomes	AF: 0.00000875	AC:2	Hom:	AN:228686	Cov:
GnomAD4 exome	AF: 0.00000349	AC:5	Hom:0	AN:1433740	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:15962	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.00	0	48444	0.0000134	1	74538

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	17
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.81	D
FuncVEP CTI	Benign	0.0013
GPN-Star LLR	N/A	-3.2
GPN-Star score	N/A	3.2
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.37	T
Mutation Taster	N/A	91/9	polymorphism
MutationAssessor	Benign	1.2	L
PhyloP100	Benign	1.9
popEVE	Benign	-3.1
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.9	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	3.2
REVEL	Benign	0.14
Sift	Benign	0.17	T
Sift4G	Uncertain	0.019	D
Varity_R	N/A	0.050
VESM-3B	Benign	-6.4

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs745662721;

hg19: chr19-41808755;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar