chr10-96565380-T-G

Variant names:

• chr10-96565380-T-G
• NM_020123.4:c.345A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020123.4(TM9SF3):​c.345A>C​(p.Glu115Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TM9SF3 NM_020123.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0650
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08058196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM9SF3	NM_020123.4	c.345A>C	p.Glu115Asp	missense_variant	Exon 3 of 15	ENST00000371142.9	NP_064508.3
TM9SF3	XM_011539976.3	c.399A>C	p.Glu133Asp	missense_variant	Exon 3 of 15		XP_011538278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM9SF3	ENST00000371142.9	c.345A>C	p.Glu115Asp	missense_variant	Exon 3 of 15	1	NM_020123.4	ENSP00000360184.4
TM9SF3	ENST00000443638.1	c.213A>C	p.Glu71Asp	missense_variant	Exon 3 of 7	3		ENSP00000401152.1
TM9SF3	ENST00000464654.1	n.307A>C		non_coding_transcript_exon_variant	Exon 3 of 6	5
TM9SF3	ENST00000649367.1	n.683A>C		non_coding_transcript_exon_variant	Exon 3 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.345A>C (p.E115D) alteration is located in exon 3 (coding exon 3) of the TM9SF3 gene. This alteration results from a A to C substitution at nucleotide position 345, causing the glutamic acid (E) at amino acid position 115 to be replaced by an aspartic acid (D). 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	Benign	0.072
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.95
DEOGEN2	Benign	0.027	T;T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.081	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.71	N;.
PhyloP100		0.065
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.60	N;N
REVEL	Benign	0.056
Sift	Benign	0.43	T;T
Sift4G	Benign	0.48	T;.
Polyphen		0.0	B;.
Vest4		0.17
MutPred		0.46		Loss of stability (P = 0.0835);.;
MVP		0.21
MPC		0.88
ClinPred		0.11	T
GERP RS		0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.051
gMVP		0.34
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

hg19: chr10-98325137;