3-196327556-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138461.4(TM4SF19):c.35G>A(p.Arg12Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

TM4SF19
NM_138461.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.898

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.15187505).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM4SF19	NM_138461.4 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 5	ENST00000273695.4	NP_612470.2	Q96DZ7-1
TM4SF19	NM_001204897.2 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 5		NP_001191826.1
TM4SF19	NM_001204898.2 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 4		NP_001191827.1	Q96DZ7-2B7ZW46
TM4SF19-DYNLT2B	NR_037950.1 link	n.193G>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.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 5	1	NM_138461.4	ENSP00000273695.4	Q96DZ7-1
TM4SF19	ENST00000446879.5 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 6	1		ENSP00000395280.1	C9JCD5
TM4SF19	ENST00000454715.5 link	c.35G>A	p.Arg12Gln	missense_variant	Exon 2 of 4	1		ENSP00000387728.1	Q96DZ7-2
TM4SF19-DYNLT2B	ENST00000442633.1 link	n.35G>A		non_coding_transcript_exon_variant	Exon 2 of 6	1		ENSP00000405973.1

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

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:

0.0000597

AC:

AN:

251082

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461500

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000225

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000125

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00124

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.:

Bravo

AF:

0.0000831

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>A (p.R12Q) 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 35, causing the arginine (R) at amino acid position 12 to be replaced by a glutamine (Q). 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

0.084

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.0068

.;.;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.73

T;T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.15

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.7

.;M;M

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.83

N;N;N

REVEL

Benign

0.064

Sift

Pathogenic

0.0

D;D;T

Sift4G

Uncertain

0.0030

D;T;T

Polyphen

0.91

P;.;D

Vest4

0.20

MutPred

0.72

Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);Gain of helix (P = 0.0425);

MVP

0.20

MPC

0.55

ClinPred

0.18

GERP RS

3.6

Varity_R

0.074

gMVP

0.39

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