Genetic Variant NM_020123.4:c.583-3delT (chr10-96559738-TA-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_020123.4(TM9SF3):c.583-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000046 in 1,542,036 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

TM9SF3
NM_020123.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.133

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6

Variant 10-96559738-TA-T is Benign according to our data. Variant chr10-96559738-TA-T is described in ClinVar as [Benign]. Clinvar id is 2991543.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TM9SF3	NM_020123.4 link	c.583-3delT		splice_region_variant, intron_variant	Intron 4 of 14	ENST00000371142.9	NP_064508.3	Q9HD45A0A024QYS2
TM9SF3	XM_011539976.3 link	c.637-3delT		splice_region_variant, intron_variant	Intron 4 of 14		XP_011538278.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
TM9SF3	ENST00000371142.9 link	c.583-3delT	splice_region_variant, intron_variant	Intron 4 of 14	1	NM_020123.4	ENSP00000360184.4	Q9HD45
TM9SF3	ENST00000443638.1 link	c.451-3delT	splice_region_variant, intron_variant	Intron 4 of 6	3		ENSP00000401152.1	Q5TB53
TM9SF3	ENST00000464654.1 link	n.545-3delT	splice_region_variant, intron_variant	Intron 4 of 5	5
TM9SF3	ENST00000649367.1 link	n.921-3delT	splice_region_variant, intron_variant	Intron 4 of 14

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

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:

0.000117

AC:

AN:

170936

AF XY:

0.000110

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000207

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.000154

Gnomad FIN exome

AF:

0.0000665

Gnomad NFE exome

AF:

0.000138

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000496

AC:

AN:

1389794

Hom.:

Cov.:

AF XY:

0.0000525

AC XY:

AN XY:

685736

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31822

American (AMR)

AF:

0.000131

AC:

AN:

38264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24864

East Asian (EAS)

AF:

0.00

AC:

AN:

38160

South Asian (SAS)

AF:

0.0000517

AC:

AN:

77368

European-Finnish (FIN)

AF:

0.0000827

AC:

AN:

48364

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.0000515

AC:

AN:

1068084

Other (OTH)

AF:

0.0000174

AC:

AN:

57508

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.350

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152242

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.13

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

Publications

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NM_020123.4:c.583-3delT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over