3-196327503-C-G

Variant names:

• chr3-196327503-C-G
• rs147419407
• NM_138461.4:c.88G>C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138461.4(TM4SF19):​c.88G>C​(p.Ala30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,614,134 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (11 hom.)
• Consequence: TM4SF19 NM_138461.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.842
• Publications: 7 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014147311).
• BS2: High Homozygotes in GnomAdExome4 at 11 AR gene

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.88G>C	p.Ala30Pro	missense	Exon 2 of 5	NP_612470.2	Q96DZ7-1
	TM4SF19	NM_001204897.2		c.88G>C	p.Ala30Pro	missense	Exon 2 of 5	NP_001191826.1
	TM4SF19	NM_001204898.2		c.88G>C	p.Ala30Pro	missense	Exon 2 of 4	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.88G>C	p.Ala30Pro	missense	Exon 2 of 5	ENSP00000273695.4	Q96DZ7-1
	TM4SF19	ENST00000446879.5	TSL:1	c.88G>C	p.Ala30Pro	missense	Exon 2 of 6	ENSP00000395280.1	C9JCD5
	TM4SF19	ENST00000454715.5	TSL:1	c.88G>C	p.Ala30Pro	missense	Exon 2 of 4	ENSP00000387728.1	Q96DZ7-2

Frequencies

GnomAD3 genomes AF: 0.00265 AC: 403 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00687

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00250 AC: 628 AN: 251278 AF XY: 0.00261

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000694

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00568

Gnomad NFE exome AF: 0.00368

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00283 AC: 4131 AN: 1461804 Hom.: 11 Cov.: 31 AF XY: 0.00286 AC XY: 2083 AN XY: 727200

African (AFR) AF: 0.000149 AC: 5 AN: 33480

American (AMR) AF: 0.000872 AC: 39 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00131 AC: 113 AN: 86258

European-Finnish (FIN) AF: 0.00531 AC: 283 AN: 53340

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5766

European-Non Finnish (NFE) AF: 0.00313 AC: 3481 AN: 1112006

Other (OTH) AF: 0.00262 AC: 158 AN: 60396

GnomAD4 genome AF: 0.00265 AC: 403 AN: 152330 Hom.: 0 Cov.: 32 AF XY: 0.00260 AC XY: 194 AN XY: 74488

African (AFR) AF: 0.000361 AC: 15 AN: 41566

American (AMR) AF: 0.00131 AC: 20 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4834

European-Finnish (FIN) AF: 0.00687 AC: 73 AN: 10620

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00414 AC: 282 AN: 68038

Other (OTH) AF: 0.00237 AC: 5 AN: 2114

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00188

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00274 AC: 332

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0085	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		0.84
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.44
MPC		1.2
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.81
gMVP		0.84
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs147419407; hg19: chr3-196054374;