dbSNP rs115496308: TMOD4:p.Ser162Thr (chr1-151172270-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_013353.3(TMOD4):c.485G>C(p.Ser162Thr) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00191 in 1,612,754 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. S162N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.010 ( 40 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 28 hom. )

Consequence

TMOD4
NM_013353.3 missense, splice_region

Scores

Splicing: ADA: 0.02070

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.00

Publications

3 publications found

Variant links:

Genes affected

TMOD4 (HGNC:11874): (tropomodulin 4) Predicted to enable tropomyosin binding activity. Predicted to be involved in actin filament organization; muscle contraction; and myofibril assembly. Located in striated muscle thin filament. [provided by Alliance of Genome Resources, Apr 2022]

TMOD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005692899).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0105 (1596/152282) while in subpopulation AFR AF = 0.0367 (1527/41552). AF 95% confidence interval is 0.0352. There are 40 homozygotes in GnomAd4. There are 775 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 40 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD4	NM_013353.3 link	c.485G>C	p.Ser162Thr	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000295314.9	NP_037485.2	Q9NZQ9-1
TMOD4	XM_011509449.2 link	c.485G>C	p.Ser162Thr	missense_variant, splice_region_variant	Exon 5 of 10		XP_011507751.1	Q9NZQ9-1
TMOD4	XM_047418672.1 link	c.485G>C	p.Ser162Thr	missense_variant, splice_region_variant	Exon 4 of 9		XP_047274628.1
TMOD4	XM_017001090.3 link	c.485G>C	p.Ser162Thr	missense_variant, splice_region_variant	Exon 5 of 8		XP_016856579.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMOD4	ENST00000295314.9 link	c.485G>C	p.Ser162Thr	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_013353.3	ENSP00000295314.4		Q9NZQ9-1

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1589

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00341

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:

0.0000588

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00263

AC:

661

AN:

251394

AF XY:

0.00178

show subpopulations

Gnomad AFR exome

AF:

0.0368

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00102

AC:

1489

AN:

1460472

Hom.:

Cov.:

AF XY:

0.000853

AC XY:

620

AN XY:

726638

show subpopulations

African (AFR)

AF:

0.0374

AC:

1251

AN:

33436

American (AMR)

AF:

0.00157

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00180

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111026

Other (OTH)

AF:

0.00229

AC:

138

AN:

60316

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

136

203

271

339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0105

AC:

1596

AN:

152282

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

775

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0367

AC:

1527

AN:

41552

American (AMR)

AF:

0.00340

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68036

Other (OTH)

AF:

0.00614

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

143

215

286

358

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000673

Hom.:

Bravo

AF:

0.0123

ESP6500AA

AF:

0.0379

AC:

167

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00344

AC:

418

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.060

Eigen

Benign

-0.060

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

MetaRNN

Benign

0.0057

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

PhyloP100

5.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.50

REVEL

Benign

0.047

Sift

Benign

0.65

Sift4G

Benign

0.62

Polyphen

0.011

Vest4

0.21

MVP

0.68

MPC

0.29

ClinPred

0.0093

GERP RS

5.7

PromoterAI

0.042

Neutral

(source)

Varity_R

0.11

gMVP

0.25

Mutation Taster

=66/34

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.021

dbscSNV1_RF

Benign

0.060

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over