2-227363746-T-G

Position:

• chr2-227363746-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.109

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=0.0039727986).
• 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	UniProt
TM4SF20	NM_024795.4	c.668A>C	p.Lys223Thr	missense_variant	4/4	ENST00000304568.4
TM4SF20	XM_011511876.3	c.467A>C	p.Lys156Thr	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TM4SF20	ENST00000304568.4	c.668A>C	p.Lys223Thr	missense_variant	4/4	1	NM_024795.4	P1

Frequencies

GnomAD3 genomes AF: 0.00461 AC: 701 AN: 152194 Hom.: 7 Cov.: 32

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.: 35 AF XY: 0.00894 AC XY: 1213 AN XY: 135700

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.: 31 AF XY: 0.00698 AC XY: 5072 AN XY: 727050

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.: 7 Cov.: 32 AF XY: 0.00524 AC XY: 390 AN XY: 74474

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.: 11

Bravo AF: 0.00449

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00754 AC: 915

Asia WGS AF: 0.00722 AC: 26 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00634

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

Jan 21, 2024

- -

TM4SF20-related disorder Benign:1

Benign, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0075	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.12
Sift	Benign	0.075	T
Sift4G	Uncertain	0.032	D
Polyphen		0.95	P
Vest4		0.18
MVP		0.38
MPC		0.042
ClinPred		0.018	T
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

Other links and lift over

dbSNP: rs137891000; hg19: chr2-228228462; COSMIC: COSV99079755;