2-227363746-T-G

Position:

chr2-227363746-T-G

Variant summary

Our verdict is Benign. Variant got -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. 12/20 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1596695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-227363746-T-G is described in Lovd as [Benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 701 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM4SF20	NM_024795.4 link	c.668A>C	p.Lys223Thr	missense_variant	4/4	ENST00000304568.4	NP_079071.2	Q53R12
TM4SF20	XM_011511876.3 link	c.467A>C	p.Lys156Thr	missense_variant	5/5		XP_011510178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM4SF20	ENST00000304568.4 link	c.668A>C	p.Lys223Thr	missense_variant	4/4	1	NM_024795.4	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

GnomAD3 exomes

AF:

0.00760

AC:

1907

AN:

251086

Hom.:

AF XY:

0.00894

AC XY:

1213

AN XY:

135700

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 SAS exome

AF:

0.0278

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

Gnomad4 AFR exome

AF:

0.00111

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.0329

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0280

Gnomad4 FIN exome

AF:

0.000562

Gnomad4 NFE exome

AF:

0.00461

Gnomad4 OTH exome

AF:

0.00831

GnomAD4 genome

AF:

0.00460

AC:

701

AN:

152312

Hom.:

Cov.:

AF XY:

0.00524

AC XY:

390

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00654

Gnomad4 ASJ

AF:

0.0354

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0246

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00454

Gnomad4 OTH

AF:

0.00567

Alfa

AF:

0.00616

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 21, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

TM4SF20-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

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

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

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

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