Genetic Variant HNRNPUL1:c.1973-102C>T (chr19-41303870-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is The variant received -14 classification points (ACMG Germline Pathogenicity v2019). BS1BS2BP4_StrongBP6_Moderate

The NM_007040.6(HNRNPUL1):c.1973-102C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.00214 (AC=3,019) in the gnomAD database across 1,408,682 control chromosomes, including 53 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.0253. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★).

Frequency

Genomes: 𝑓 0.0037 ( 9 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 44 hom. )

Consequence

HNRNPUL1
NM_007040.6 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.92

Publications

0 publications found

Variant links:

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]

HNRNPUL1 links:

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

TGFB1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_007040.6, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Benign. The variant received -14 points.

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BP6

ClinVar 1-star benign — moderate (BP6); ClinVar germline classification: Benign/Likely Benign, 1 star(s).

BS1

GnomAD effective popmax AF above BS1 threshold — greater than expected for disorder; GnomAD effective popmax AF = 0.0253 vs gene BS1 threshold 0.015.

BS2

≥2 homozygotes in gnomAD — observed in healthy adults (BS2); GnomAD homozygous count = 53.; Very high cumulative gnomAD AC = 3019 (any gene).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNRNPUL1	NM_007040.6	MANE Select	c.1973-102C>T	intron	N/A	NP_008971.2
HNRNPUL1	NM_001439168.1		c.1973-102C>T	intron	N/A	NP_001426097.1
HNRNPUL1	NM_001439167.1		c.1973-102C>T	intron	N/A	NP_001426096.1	Q9BUJ2-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HNRNPUL1	ENST00000392006.8	TSL:1 MANE Select	c.1973-102C>T	intron	N/A	ENSP00000375863.2	Q9BUJ2-1
HNRNPUL1	ENST00000602130.5	TSL:1	c.1973-102C>T	intron	N/A	ENSP00000470687.1	Q9BUJ2-2
HNRNPUL1	ENST00000352456.7	TSL:1	c.1673-102C>T	intron	N/A	ENSP00000340857.3	A0A0A0MRA5

Frequencies

GnomAD3 genomes

AF:

0.00360

AC:

548

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00946

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000519

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000198

Gnomad SAS

AF:

0.0273

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000107

Gnomad OTH

AF:

0.00383

GnomAD4 exome

AF:

0.00195

AC:

2460

AN:

1256364

Hom.:

AF XY:

0.00261

AC XY:

1627

AN XY:

622600

show subpopulations

African (AFR)

AF:

0.0116

AC:

328

AN:

28240

American (AMR)

AF:

0.000900

AC:

AN:

32416

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19882

East Asian (EAS)

AF:

0.0000458

AC:

AN:

38456

South Asian (SAS)

AF:

0.0263

AC:

1844

AN:

70092

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46132

Middle Eastern (MID)

AF:

0.00438

AC:

AN:

4796

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

963554

Other (OTH)

AF:

0.00264

AC:

139

AN:

52796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

142

284

425

567

709

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

144

192

240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00368

AC:

559

AN:

152318

Hom.:

Cov.:

AF XY:

0.00388

AC XY:

289

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.00963

AC:

400

AN:

41566

American (AMR)

AF:

0.000519

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000198

AC:

AN:

5182

South Asian (SAS)

AF:

0.0280

AC:

135

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000107

AC:

AN:

68030

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

106

132

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00305

Hom.:

Bravo

AF:

0.00331

Asia WGS

AF:

0.00999

AC:

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0000330

AC:

AN:

122506

Turkish Variome

AF:

0.00129

AC:

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.000112

AC:

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.00299

AC:

AN:

2342

Hom.:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.99

(source)

DANN

Benign

0.76

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism

(source)

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

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over