19-41302898-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_007040.6(HNRNPUL1):c.1921G>A(p.Gly641Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000279 in 1,541,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: HNRNPUL1 NM_007040.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, HNRNPUL1
• BP4: Computational evidence support a benign effect (MetaRNN=0.09241268).
• BS2: High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HNRNPUL1	NM_007040.6	c.1921G>A	p.Gly641Ser	missense_variant	12/15	ENST00000392006.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HNRNPUL1	ENST00000392006.8	c.1921G>A	p.Gly641Ser	missense_variant	12/15	1	NM_007040.6	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152150 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

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

GnomAD3 exomes AF: 0.000115 AC: 22 AN: 191312 Hom.: 0 AF XY: 0.000118 AC XY: 12 AN XY: 101382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000808

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000979

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000238 AC: 33 AN: 1388762 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 16 AN XY: 683318

Gnomad4 AFR exome AF: 0.0000322

Gnomad4 AMR exome AF: 0.0000887

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000281

Gnomad4 SAS exome AF: 0.0000134

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000139

Gnomad4 OTH exome AF: 0.0000175

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152268 Hom.: 0 Cov.: 31 AF XY: 0.000121 AC XY: 9 AN XY: 74458

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.0000416

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000150 AC: 18

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2023

The c.1921G>A (p.G641S) alteration is located in exon 12 (coding exon 12) of the HNRNPUL1 gene. This alteration results from a G to A substitution at nucleotide position 1921, causing the glycine (G) at amino acid position 641 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.040
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.070	T;.;T;.;.;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;.;D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.092	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.015	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;.;D;D;.;.;D
REVEL	Uncertain	0.58
Sift	Benign	0.092	T;.;T;T;.;.;T
Sift4G	Benign	0.10	T;T;T;T;D;T;T
Polyphen		1.0	.;D;D;D;D;D;D
Vest4		0.30
MVP		0.84
MPC		0.71
ClinPred		0.20	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.38
gMVP		0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs143909179; hg19: chr19-41808803; COSMIC: COSV54561331; COSMIC: COSV54561331;