chr3-196327544-C-T

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

3
6
10

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-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]

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
TM4SF19NM_138461.4 linkc.47G>A p.Arg16His missense_variant Exon 2 of 5 ENST00000273695.4 NP_612470.2 Q96DZ7-1
TM4SF19NM_001204897.2 linkc.47G>A p.Arg16His missense_variant Exon 2 of 5 NP_001191826.1
TM4SF19NM_001204898.2 linkc.47G>A p.Arg16His missense_variant Exon 2 of 4 NP_001191827.1 Q96DZ7-2B7ZW46
TM4SF19-DYNLT2BNR_037950.1 linkn.205G>A non_coding_transcript_exon_variant Exon 2 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TM4SF19ENST00000273695.4 linkc.47G>A p.Arg16His missense_variant Exon 2 of 5 1 NM_138461.4 ENSP00000273695.4 Q96DZ7-1
TM4SF19ENST00000446879.5 linkc.47G>A p.Arg16His missense_variant Exon 2 of 6 1 ENSP00000395280.1 C9JCD5
TM4SF19ENST00000454715.5 linkc.47G>A p.Arg16His missense_variant Exon 2 of 4 1 ENSP00000387728.1 Q96DZ7-2
TM4SF19-DYNLT2BENST00000442633.1 linkn.47G>A non_coding_transcript_exon_variant Exon 2 of 6 1 ENSP00000405973.1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
152176
Hom.:
0
Cov.:
32
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:
3
AN:
251186
Hom.:
0
AF XY:
0.0000147
AC XY:
2
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:
16
AN:
1461688
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
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:
0
AN:
152294
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
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:
2
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
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.050
.;.;T
Eigen
Uncertain
0.46
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Benign
0.84
T;T;T
M_CAP
Uncertain
0.088
D
MetaRNN
Pathogenic
0.83
D;D;D
MetaSVM
Benign
-0.66
T
MutationAssessor
Pathogenic
3.2
.;M;M
PrimateAI
Benign
0.33
T
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
D
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.

Other links and lift over

dbSNP: rs777823066; hg19: chr3-196054415; COSMIC: COSV56556626; COSMIC: COSV56556626; API