3-196327032-C-A

Variant names:

• chr3-196327032-C-A
• rs150423371
• NM_138461.4:c.202G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_138461.4(TM4SF19):​c.202G>T​(p.Val68Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000232 in 1,601,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: TM4SF19 NM_138461.4 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.81
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138461.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM4SF19	NM_138461.4	MANE Select	c.202G>T	p.Val68Leu	missense splice_region	Exon 3 of 5	NP_612470.2	Q96DZ7-1
	TM4SF19	NM_001204897.2		c.202G>T	p.Val68Leu	missense splice_region	Exon 3 of 5	NP_001191826.1
	TM4SF19	NM_001204898.2		c.201+358G>T		intron	N/A	NP_001191827.1	Q96DZ7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM4SF19	ENST00000273695.4	TSL:1 MANE Select	c.202G>T	p.Val68Leu	missense splice_region	Exon 3 of 5	ENSP00000273695.4	Q96DZ7-1
	TM4SF19	ENST00000446879.5	TSL:1	c.202G>T	p.Val68Leu	missense splice_region	Exon 3 of 6	ENSP00000395280.1	C9JCD5
	TM4SF19	ENST00000454715.5	TSL:1	c.201+358G>T		intron	N/A	ENSP00000387728.1	Q96DZ7-2

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000231 AC: 58 AN: 251280 AF XY: 0.000191

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000242 AC: 350 AN: 1448810 Hom.: 0 Cov.: 30 AF XY: 0.000234 AC XY: 168 AN XY: 718244

African (AFR) AF: 0.000120 AC: 4 AN: 33270

American (AMR) AF: 0.000651 AC: 29 AN: 44552

Ashkenazi Jewish (ASJ) AF: 0.000154 AC: 4 AN: 26050

East Asian (EAS) AF: 0.00 AC: 0 AN: 39308

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85990

European-Finnish (FIN) AF: 0.0000563 AC: 3 AN: 53310

Middle Eastern (MID) AF: 0.00331 AC: 19 AN: 5734

European-Non Finnish (NFE) AF: 0.000229 AC: 252 AN: 1100808

Other (OTH) AF: 0.000636 AC: 38 AN: 59788

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74434

African (AFR) AF: 0.0000963 AC: 4 AN: 41540

American (AMR) AF: 0.000196 AC: 3 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68012

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000274 Hom.: 0

Bravo AF: 0.000249

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		3.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.24
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.61
MutPred		0.56		Loss of catalytic residue at V68 (P = 0.2577)
MVP		0.38
MPC		0.82
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.39
gMVP		0.75
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
Splicevardb		3.0
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150423371; hg19: chr3-196053903;