Genetic Variant TM9SF3:p.Ser560Gly (chr10-96527237-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_020123.4(TM9SF3):c.1678A>G(p.Ser560Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TM9SF3
NM_020123.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.92

Publications

0 publications found

Variant links:

Genes affected

TM9SF3 (HGNC:21529): (transmembrane 9 superfamily member 3) Predicted to be involved in protein localization to membrane. Predicted to be located in exocytic vesicle. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

TM9SF3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM9SF3	NM_020123.4 link	c.1678A>G	p.Ser560Gly	missense_variant	Exon 14 of 15	ENST00000371142.9	NP_064508.3	Q9HD45A0A024QYS2
TM9SF3	XM_011539976.3 link	c.1732A>G	p.Ser578Gly	missense_variant	Exon 14 of 15		XP_011538278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TM9SF3	ENST00000371142.9 link	c.1678A>G	p.Ser560Gly	missense_variant	Exon 14 of 15	1	NM_020123.4	ENSP00000360184.4	Q9HD45
TM9SF3	ENST00000485093.1 link	n.329A>G		non_coding_transcript_exon_variant	Exon 3 of 4	5
TM9SF3	ENST00000649367.1 link	n.2016A>G		non_coding_transcript_exon_variant	Exon 14 of 15

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459224

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725924

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26058

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.00

AC:

AN:

86056

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1110802

Other (OTH)

AF:

0.00

AC:

AN:

60198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 16, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1678A>G (p.S560G) alteration is located in exon 14 (coding exon 14) of the TM9SF3 gene. This alteration results from a A to G substitution at nucleotide position 1678, causing the serine (S) at amino acid position 560 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Uncertain

0.024

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.054

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.24

Sift

Uncertain

0.014

Sift4G

Uncertain

0.060

Polyphen

0.85

Vest4

0.64

MutPred

0.57

Loss of glycosylation at S560 (P = 0.0767);

MVP

0.24

MPC

1.6

ClinPred

0.97

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.73

Mutation Taster

=13/87

disease causing

(source)

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

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10-96527237-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over