chr2-227363746-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024795.4(TM4SF20):c.668A>C(p.Lys223Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00616 in 1,613,826 control chromosomes in the GnomAD database, including 114 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0063 ( 107 hom. )

Consequence

TM4SF20
NM_024795.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.109

Publications

10 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=0.0039727986).

BP6

Variant 2-227363746-T-G is Benign according to our data. Variant chr2-227363746-T-G is described in ClinVar as Benign. ClinVar VariationId is 1596695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0046 (701/152312) while in subpopulation SAS AF = 0.0246 (119/4830). AF 95% confidence interval is 0.021. There are 7 homozygotes in GnomAd4. There are 390 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 701 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024795.4. 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
	TM4SF20	NM_024795.4	MANE Select	c.668A>C	p.Lys223Thr	missense	Exon 4 of 4	NP_079071.2	Q53R12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TM4SF20	ENST00000304568.4	TSL:1 MANE Select	c.668A>C	p.Lys223Thr	missense	Exon 4 of 4	ENSP00000303028.3	Q53R12

Frequencies

GnomAD3 genomes

AF:

0.00461

AC:

701

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00655

Gnomad ASJ

AF:

0.0354

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0246

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00454

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00760

AC:

1907

AN:

251086

AF XY:

0.00894

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00261

Gnomad ASJ exome

AF:

0.0338

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00489

Gnomad OTH exome

AF:

0.00915

GnomAD4 exome

AF:

0.00632

AC:

9240

AN:

1461514

Hom.:

107

Cov.:

AF XY:

0.00698

AC XY:

5072

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33434

American (AMR)

AF:

0.00293

AC:

131

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.0329

AC:

859

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.0280

AC:

2415

AN:

86200

European-Finnish (FIN)

AF:

0.000562

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.0245

AC:

141

AN:

5766

European-Non Finnish (NFE)

AF:

0.00461

AC:

5124

AN:

1111864

Other (OTH)

AF:

0.00831

AC:

502

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

479

958

1436

1915

2394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

226

452

678

904

1130

<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:

0.00460

AC:

701

AN:

152312

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

390

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

41572

American (AMR)

AF:

0.00654

AC:

100

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0354

AC:

123

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.0246

AC:

119

AN:

4830

European-Finnish (FIN)

AF:

0.000283

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00454

AC:

309

AN:

68032

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00606

Hom.:

Bravo

AF:

0.00449

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00754

AC:

915

Asia WGS

AF:

0.00722

AC:

AN:

3478

EpiCase

AF:

0.00622

EpiControl

AF:

0.00634

ClinVar

ClinVar submissions

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

0.18

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0075

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.081

LIST_S2

Benign

0.59

MetaRNN

Benign

0.0040

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

-0.11

PrimateAI

Benign

0.28

PROVEAN

Benign

-2.0

REVEL

Benign

0.12

Sift

Benign

0.075

Sift4G

Uncertain

0.032

Polyphen

0.95

Vest4

0.18

MVP

0.38

MPC

0.042

ClinPred

0.018

GERP RS

2.0

Varity_R

0.087

gMVP

0.13

Mutation Taster

=94/6

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over