rs370403938

Variant names:

• chr10-96551285-T-C
• rs370403938
• NM_020123.4:c.919A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_020123.4(TM9SF3):​c.919A>G​(p.Ile307Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TM9SF3 NM_020123.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.79
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26552624).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM9SF3	NM_020123.4	c.919A>G	p.Ile307Val	missense_variant	Exon 7 of 15	ENST00000371142.9	NP_064508.3
TM9SF3	XM_011539976.3	c.973A>G	p.Ile325Val	missense_variant	Exon 7 of 15		XP_011538278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TM9SF3	ENST00000371142.9	c.919A>G	p.Ile307Val	missense_variant	Exon 7 of 15	1	NM_020123.4	ENSP00000360184.4
TM9SF3	ENST00000490192.1	n.143A>G		non_coding_transcript_exon_variant	Exon 2 of 4	4
TM9SF3	ENST00000649367.1	n.1257A>G		non_coding_transcript_exon_variant	Exon 7 of 15
TM9SF3	ENST00000443638.1	c.*26A>G		downstream_gene_variant		3		ENSP00000401152.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 250138 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460304 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 726504

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39574

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111506

Other (OTH) AF: 0.00 AC: 0 AN: 60350

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.919A>G (p.I307V) alteration is located in exon 7 (coding exon 7) of the TM9SF3 gene. This alteration results from a A to G substitution at nucleotide position 919, causing the isoleucine (I) at amino acid position 307 to be replaced by a valine (V). 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	0.073
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.27
Eigen_PC	Benign	0.0024
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N
PhyloP100		7.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	0.0	N
REVEL	Benign	0.23
Sift	Benign	0.49	T
Sift4G	Benign	0.82	T
Polyphen		0.0020	B
Vest4		0.54
MVP		0.21
MPC		0.81
ClinPred		0.87	D
GERP RS		5.3
Varity_R		0.075
gMVP		0.19
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

dbSNP: rs370403938; hg19: chr10-98311042;