2-227379189-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000304568.4(TM4SF20):c.80C>T(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.127 in 1,613,730 control chromosomes in the GnomAD database, including 13,573 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A27A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.11 ( 1045 hom., cov: 33)

Exomes 𝑓: 0.13 ( 12528 hom. )

Consequence

TM4SF20
ENST00000304568.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.102

Publications

27 publications found

Variant links:

Genes affected

TM4SF20 (HGNC:26230): (transmembrane 4 L six family member 20) 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. Knockout of the homologous gene in mouse results in a neurobehavioral phenotype with suggested enhanced motor coordination. A deletion mutation in the human gene is associated with specific language impairment-5. [provided by RefSeq, Jul 2016]

TM4SF20 Gene-Disease associations (from GenCC):

specific language impairment 5
Inheritance: AD Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

TM4SF20 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022626221).

BP6

Variant 2-227379189-G-A is Benign according to our data. Variant chr2-227379189-G-A is described in ClinVar as Benign. ClinVar VariationId is 1166272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000304568.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM4SF20	NM_024795.4	MANE Select	c.80C>T	p.Ala27Val	missense	Exon 1 of 4	NP_079071.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM4SF20	ENST00000304568.4	TSL:1 MANE Select	c.80C>T	p.Ala27Val	missense	Exon 1 of 4	ENSP00000303028.3
	TM4SF20	ENST00000449706.1	TSL:4	c.*37C>T		downstream_gene	N/A	ENSP00000416565.1

Frequencies

GnomAD3 genomes

AF:

0.107

AC:

16249

AN:

152000

Hom.:

1046

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0238

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.0964

Gnomad ASJ

AF:

0.159

Gnomad EAS

AF:

0.190

Gnomad SAS

AF:

0.100

Gnomad FIN

AF:

0.156

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.141

Gnomad OTH

AF:

0.128

GnomAD2 exomes

AF:

0.122

AC:

30744

AN:

251312

AF XY:

0.125

show subpopulations

Gnomad AFR exome

AF:

0.0230

Gnomad AMR exome

AF:

0.0729

Gnomad ASJ exome

AF:

0.150

Gnomad EAS exome

AF:

0.186

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.139

Gnomad OTH exome

AF:

0.136

GnomAD4 exome

AF:

0.130

AC:

189304

AN:

1461612

Hom.:

12528

Cov.:

AF XY:

0.130

AC XY:

94218

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0209

AC:

698

AN:

33476

American (AMR)

AF:

0.0737

AC:

3295

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.144

AC:

3766

AN:

26136

East Asian (EAS)

AF:

0.179

AC:

7099

AN:

39698

South Asian (SAS)

AF:

0.0911

AC:

7855

AN:

86242

European-Finnish (FIN)

AF:

0.157

AC:

8381

AN:

53364

Middle Eastern (MID)

AF:

0.142

AC:

820

AN:

5762

European-Non Finnish (NFE)

AF:

0.135

AC:

149668

AN:

1111828

Other (OTH)

AF:

0.128

AC:

7722

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

5442

10884

16327

21769

27211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5190

10380

15570

20760

25950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.107

AC:

16251

AN:

152118

Hom.:

1045

Cov.:

AF XY:

0.107

AC XY:

7989

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.0237

AC:

986

AN:

41528

American (AMR)

AF:

0.0965

AC:

1476

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

552

AN:

3472

East Asian (EAS)

AF:

0.191

AC:

987

AN:

5168

South Asian (SAS)

AF:

0.100

AC:

484

AN:

4822

European-Finnish (FIN)

AF:

0.156

AC:

1642

AN:

10554

Middle Eastern (MID)

AF:

0.133

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.141

AC:

9555

AN:

67968

Other (OTH)

AF:

0.128

AC:

270

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.571

Heterozygous variant carriers

461

922

1384

1845

2306

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

188

376

564

752

940

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.127

Hom.:

4159

Bravo

AF:

0.0998

TwinsUK

AF:

0.133

AC:

492

ALSPAC

AF:

0.124

AC:

479

ESP6500AA

AF:

0.0261

AC:

115

ESP6500EA

AF:

0.141

AC:

1209

ExAC

AF:

0.122

AC:

14819

Asia WGS

AF:

0.142

AC:

491

AN:

3478

EpiCase

AF:

0.150

EpiControl

AF:

0.146

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

TM4SF20-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.4

(source)

DANN

Benign

0.073

DEOGEN2

Benign

0.0028

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.041

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

0.10

PrimateAI

Benign

0.30

PROVEAN

Benign

1.5

REVEL

Benign

0.076

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.96

Vest4

0.030

MPC

0.011

ClinPred

0.016

GERP RS

1.8

PromoterAI

-0.023

Neutral

(source)

Varity_R

0.022

gMVP

0.25

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over