Variant 20-32143015-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The ENST00000398022.7(TM9SF4):c.562T>C(p.Tyr188His) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,613,698 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TM9SF4
ENST00000398022.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.67

Variant links:

Genes affected

TM9SF4 (HGNC:30797): (transmembrane 9 superfamily member 4) Involved in several processes, including positive regulation of protein localization; regulation of intracellular pH; and vacuolar proton-transporting V-type ATPase complex assembly. Located in Golgi apparatus and early endosome. [provided by Alliance of Genome Resources, Apr 2022]

TM9SF4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TM9SF4. . Gene score misZ 2.9598 (greater than the threshold 3.09). Trascript score misZ 4.0297 (greater than threshold 3.09). GenCC has associacion of gene with autism spectrum disorder.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TM9SF4	NM_014742.4 linkuse as main transcript	c.562T>C	p.Tyr188His	missense_variant	6/18	ENST00000398022.7	NP_055557.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TM9SF4	ENST00000398022.7 linkuse as main transcript	c.562T>C	p.Tyr188His	missense_variant	6/18	1	NM_014742.4	ENSP00000381104	P1
TM9SF4	ENST00000217315.9 linkuse as main transcript	c.511T>C	p.Tyr171His	missense_variant	6/18	2		ENSP00000217315

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461500

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

TM9SF4-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 06, 2023

The TM9SF4 c.562T>C variant is predicted to result in the amino acid substitution p.Tyr188His. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0027

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.017

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

0.025

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D

M_CAP

Benign

0.0075

MetaRNN

Uncertain

0.57

D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.035

N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

0.22

N;N

REVEL

Benign

0.15

Sift

Benign

0.53

T;T

Sift4G

Benign

0.56

T;T

Polyphen

0.0010

B;.

Vest4

0.85

MutPred

0.57

Gain of disorder (P = 0.03);.;

MVP

0.21

MPC

0.96

ClinPred

0.80

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.60

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