rs7574414

Positions:

• chr2-227379189-G-A
• chr2-227379189-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024795.4(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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.11 (1045 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12528 hom.)
• Consequence: TM4SF20 NM_024795.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.102

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM4SF20	NM_024795.4	c.80C>T	p.Ala27Val	missense_variant	1/4	ENST00000304568.4	NP_079071.2
TM4SF20	XM_011511876.3	c.-205+2400C>T		intron_variant			XP_011510178.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM4SF20	ENST00000304568.4	c.80C>T	p.Ala27Val	missense_variant	1/4	1	NM_024795.4	ENSP00000303028.3
TM4SF20	ENST00000449706.1	c.*37C>T		downstream_gene_variant		4		ENSP00000416565.1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16249 AN: 152000 Hom.: 1046 Cov.: 33

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

GnomAD3 exomes AF: 0.122 AC: 30744 AN: 251312 Hom.: 2094 AF XY: 0.125 AC XY: 16922 AN XY: 135822

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 SAS exome AF: 0.0924

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.: 32 AF XY: 0.130 AC XY: 94218 AN XY: 727098

Gnomad4 AFR exome AF: 0.0209

Gnomad4 AMR exome AF: 0.0737

Gnomad4 ASJ exome AF: 0.144

Gnomad4 EAS exome AF: 0.179

Gnomad4 SAS exome AF: 0.0911

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.107 AC: 16251 AN: 152118 Hom.: 1045 Cov.: 33 AF XY: 0.107 AC XY: 7989 AN XY: 74354

Gnomad4 AFR AF: 0.0237

Gnomad4 AMR AF: 0.0965

Gnomad4 ASJ AF: 0.159

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.100

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.141

Gnomad4 OTH AF: 0.128

Alfa AF: 0.134 Hom.: 2898

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

TM4SF20-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 22, 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	0.12
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	2.4
DANN	Benign	0.073
DEOGEN2	Benign	0.0028	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.041	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.076
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.96	D
Vest4		0.030
MPC		0.011
ClinPred		0.016	T
GERP RS		1.8
Varity_R		0.022
gMVP		0.25

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

Other links and lift over

dbSNP: rs7574414; hg19: chr2-228243905; COSMIC: COSV58818572; COSMIC: COSV58818572;