3-196327574-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000273695.4(TM4SF19):​c.17G>T​(p.Cys6Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

TM4SF19
ENST00000273695.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.881
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TM4SF19NM_138461.4 linkuse as main transcriptc.17G>T p.Cys6Phe missense_variant 2/5 ENST00000273695.4 NP_612470.2 Q96DZ7-1
TM4SF19NM_001204897.2 linkuse as main transcriptc.17G>T p.Cys6Phe missense_variant 2/5 NP_001191826.1
TM4SF19NM_001204898.2 linkuse as main transcriptc.17G>T p.Cys6Phe missense_variant 2/4 NP_001191827.1 Q96DZ7-2B7ZW46
TM4SF19-DYNLT2BNR_037950.1 linkuse as main transcriptn.175G>T non_coding_transcript_exon_variant 2/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TM4SF19ENST00000273695.4 linkuse as main transcriptc.17G>T p.Cys6Phe missense_variant 2/51 NM_138461.4 ENSP00000273695.4 Q96DZ7-1
TM4SF19ENST00000446879.5 linkuse as main transcriptc.17G>T p.Cys6Phe missense_variant 2/61 ENSP00000395280.1 C9JCD5
TM4SF19ENST00000454715.5 linkuse as main transcriptc.17G>T p.Cys6Phe missense_variant 2/41 ENSP00000387728.1 Q96DZ7-2
TM4SF19-DYNLT2BENST00000442633.1 linkuse as main transcriptn.17G>T non_coding_transcript_exon_variant 2/61 ENSP00000405973.1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152078
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000720
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:
0.0000438
AC:
11
AN:
250872
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135696
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000318
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000103
AC:
15
AN:
1461282
Hom.:
0
Cov.:
36
AF XY:
0.00000688
AC XY:
5
AN XY:
726968
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000313
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152078
Hom.:
0
Cov.:
33
AF XY:
0.0000942
AC XY:
7
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000720
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
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000907

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 21, 2023The c.17G>T (p.C6F) alteration is located in exon 2 (coding exon 1) of the TM4SF19 gene. This alteration results from a G to T substitution at nucleotide position 17, causing the cysteine (C) at amino acid position 6 to be replaced by a phenylalanine (F). 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
0.073
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
18
DANN
Benign
0.90
DEOGEN2
Benign
0.0069
.;.;T
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.54
FATHMM_MKL
Benign
0.12
N
LIST_S2
Benign
0.48
T;T;T
M_CAP
Benign
0.0088
T
MetaRNN
Benign
0.084
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Uncertain
2.1
.;M;M
MutationTaster
Benign
1.0
N;N;N
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.73
N;N;N
REVEL
Benign
0.042
Sift
Uncertain
0.021
D;T;T
Sift4G
Uncertain
0.024
D;T;T
Polyphen
0.87
P;.;B
Vest4
0.35
MutPred
0.14
Loss of catalytic residue at P5 (P = 0.077);Loss of catalytic residue at P5 (P = 0.077);Loss of catalytic residue at P5 (P = 0.077);
MVP
0.22
MPC
0.67
ClinPred
0.042
T
GERP RS
2.7
Varity_R
0.066
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.32
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.32
Position offset: -8

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: rs1375597127; hg19: chr3-196054445; API