2-227363778-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_024795.4(TM4SF20):c.636C>T(p.Ile212=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0019 in 1,614,082 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (8 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (40 hom.)
• Consequence: TM4SF20 NM_024795.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.320

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 2-227363778-G-A is Benign according to our data. Variant chr2-227363778-G-A is described in ClinVar as [Benign]. Clinvar id is 1600994.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.32 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.00178 (2609/1461872) while in subpopulation EAS AF= 0.0164 (651/39698). AF 95% confidence interval is 0.0154. There are 40 homozygotes in gnomad4_exome. There are 1288 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 461 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TM4SF20	NM_024795.4	c.636C>T	p.Ile212=	synonymous_variant	4/4	ENST00000304568.4
TM4SF20	XM_011511876.3	c.435C>T	p.Ile145=	synonymous_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM4SF20	ENST00000304568.4	c.636C>T	p.Ile212=	synonymous_variant	4/4	1	NM_024795.4	P1

Frequencies

GnomAD3 genomes AF: 0.00303 AC: 461 AN: 152092 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00848

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00380 AC: 955 AN: 251410 Hom.: 18 AF XY: 0.00379 AC XY: 515 AN XY: 135868

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00614

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0328

Gnomad NFE exome AF: 0.000871

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00178 AC: 2609 AN: 1461872 Hom.: 40 Cov.: 31 AF XY: 0.00177 AC XY: 1288 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0164

Gnomad4 SAS exome AF: 0.000417

Gnomad4 FIN exome AF: 0.0289

Gnomad4 NFE exome AF: 0.000268

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152210 Hom.: 8 Cov.: 32 AF XY: 0.00460 AC XY: 342 AN XY: 74398

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00850

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0343

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000899 Hom.: 1

Bravo AF: 0.000389

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 07, 2023

- -

TM4SF20-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 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
BayesDel_noAF	Benign	-0.55
Cadd	Benign	3.1
Dann	Benign	0.83

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: rs151133854; hg19: chr2-228228494;