2-227366120-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_024795.4(TM4SF20):c.374A>G(p.Asn125Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,611,264 control chromosomes in the GnomAD database, including 1,061 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 (★).

• Frequency:
  • Genomes: 𝑓 0.043 (370 hom., cov: 32)
  • Exomes 𝑓: 0.011 (691 hom.)
• Consequence: TM4SF20 NM_024795.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.374

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018193126).
• BP6: Variant 2-227366120-T-C is Benign according to our data. Variant chr2-227366120-T-C is described in ClinVar as [Benign]. Clinvar id is 1167997.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TM4SF20	NM_024795.4	c.374A>G	p.Asn125Ser	missense_variant	3/4	ENST00000304568.4
TM4SF20	XM_011511876.3	c.173A>G	p.Asn58Ser	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM4SF20	ENST00000304568.4	c.374A>G	p.Asn125Ser	missense_variant	3/4	1	NM_024795.4	P1

Frequencies

GnomAD3 genomes AF: 0.0429 AC: 6534 AN: 152190 Hom.: 371 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0188

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0413

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00300

Gnomad OTH AF: 0.0349

GnomAD3 exomes AF: 0.0278 AC: 6898 AN: 248244 Hom.: 351 AF XY: 0.0252 AC XY: 3379 AN XY: 134078

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.00881

Gnomad ASJ exome AF: 0.00645

Gnomad EAS exome AF: 0.146

Gnomad SAS exome AF: 0.0202

Gnomad FIN exome AF: 0.0398

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0112 AC: 16402 AN: 1458956 Hom.: 691 Cov.: 31 AF XY: 0.0111 AC XY: 8075 AN XY: 725652

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.00980

Gnomad4 ASJ exome AF: 0.00792

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.0186

Gnomad4 FIN exome AF: 0.0360

Gnomad4 NFE exome AF: 0.00160

Gnomad4 OTH exome AF: 0.0208

GnomAD4 genome AF: 0.0430 AC: 6542 AN: 152308 Hom.: 370 Cov.: 32 AF XY: 0.0451 AC XY: 3359 AN XY: 74470

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0188

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0413

Gnomad4 NFE AF: 0.00298

Gnomad4 OTH AF: 0.0350

Alfa AF: 0.0138 Hom.: 171

Bravo AF: 0.0452

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.112 AC: 493

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.0286 AC: 3468

Asia WGS AF: 0.0850 AC: 296 AN: 3476

EpiCase AF: 0.00289

EpiControl AF: 0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.025
Dann	Benign	0.20
DEOGEN2	Benign	0.0026	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.075	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.032
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.010	B
Vest4		0.029
MPC		0.010
ClinPred		0.0014	T
GERP RS		-5.0
Varity_R		0.025
gMVP		0.067

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: rs80305648; hg19: chr2-228230836; COSMIC: COSV58818898;