chr10-96522294-C-A

Variant names:

• chr10-96522294-C-A
• rs150067149
• NM_020123.4:c.1739G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020123.4(TM9SF3):​c.1739G>T​(p.Arg580Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R580Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TM9SF3 NM_020123.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 3 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM9SF3	NM_020123.4	c.1739G>T	p.Arg580Leu	missense_variant	Exon 15 of 15	ENST00000371142.9	NP_064508.3
TM9SF3	XM_011539976.3	c.1793G>T	p.Arg598Leu	missense_variant	Exon 15 of 15		XP_011538278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM9SF3	ENST00000371142.9	c.1739G>T	p.Arg580Leu	missense_variant	Exon 15 of 15	1	NM_020123.4	ENSP00000360184.4
TM9SF3	ENST00000485093.1	n.390G>T		non_coding_transcript_exon_variant	Exon 4 of 4	5
TM9SF3	ENST00000649367.1	n.2077G>T		non_coding_transcript_exon_variant	Exon 15 of 15

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Benign	-0.61	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.021	D
Polyphen		0.93	P
Vest4		0.90
MutPred		0.69		Loss of MoRF binding (P = 0.0047);
MVP		0.68
MPC		2.0
ClinPred		0.98	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.84
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.23		Position offset: 36

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150067149; hg19: chr10-98282051;