chr3-196327544-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_138461.4(TM4SF19):c.47G>A(p.Arg16His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TM4SF19
NM_138461.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.13

Variant links:

Genes affected

TM4SF19 (HGNC:25167): (transmembrane 4 L six family member 19) The protein encoded by this gene is a member of the four-transmembrane L6 superfamily. Members of this family function in various cellular processes including cell proliferation, motility, and adhesion via their interactions with integrins. In human brain tissue, this gene is expressed at high levels in the parietal lobe, occipital lobe, hippocampus, pons, white matter, corpus callosum, and cerebellum. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2017]

TM4SF19 links:

TM4SF19-DYNLT2B (HGNC:49190): (TM4SF19-DYNLT2B readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring transmembrane 4 L six family member 19 (TM4SF19) and Tctex1 domain containing 2 (TCTEX1D2) genes on chromosome 3. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus not expected to produce a protein product. [provided by RefSeq, Mar 2011]

TM4SF19-DYNLT2B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM4SF19	NM_138461.4 link	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 5	ENST00000273695.4	NP_612470.2	Q96DZ7-1
TM4SF19	NM_001204897.2 link	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 5		NP_001191826.1
TM4SF19	NM_001204898.2 link	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 4		NP_001191827.1	Q96DZ7-2B7ZW46
TM4SF19-DYNLT2B	NR_037950.1 link	n.205G>A		non_coding_transcript_exon_variant	Exon 2 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TM4SF19	ENST00000273695.4 link	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 5	1	NM_138461.4	ENSP00000273695.4	Q96DZ7-1
TM4SF19	ENST00000446879.5 link	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 6	1		ENSP00000395280.1	C9JCD5
TM4SF19	ENST00000454715.5 link	c.47G>A	p.Arg16His	missense_variant	Exon 2 of 4	1		ENSP00000387728.1	Q96DZ7-2
TM4SF19-DYNLT2B	ENST00000442633.1 link	n.47G>A		non_coding_transcript_exon_variant	Exon 2 of 6	1		ENSP00000405973.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152176

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251186

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727158

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74468

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47G>A (p.R16H) alteration is located in exon 2 (coding exon 1) of the TM4SF19 gene. This alteration results from a G to A substitution at nucleotide position 47, causing the arginine (R) at amino acid position 16 to be replaced by a histidine (H). 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

0.10

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.050

.;.;T

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.84

T;T;T

M_CAP

Uncertain

0.088

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Benign

-0.66

MutationAssessor

Pathogenic

3.2

.;M;M

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.79

N;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0020

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.40

MutPred

0.90

Gain of catalytic residue at L18 (P = 0.0488);Gain of catalytic residue at L18 (P = 0.0488);Gain of catalytic residue at L18 (P = 0.0488);

MVP

0.47

MPC

1.0

ClinPred

0.74

GERP RS

4.0

Varity_R

0.15

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over