Genetic Variant TMOD4:p.Ser162Asn (chr1-151172270-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013353.3(TMOD4):c.485G>A(p.Ser162Asn) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000026 in 1,612,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

TMOD4
NM_013353.3 missense, splice_region

Scores

Splicing: ADA: 0.03505

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.052868903).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMOD4	NM_013353.3 link	c.485G>A	p.Ser162Asn	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000295314.9	NP_037485.2	Q9NZQ9-1
TMOD4	XM_011509449.2 link	c.485G>A	p.Ser162Asn	missense_variant, splice_region_variant	Exon 5 of 10		XP_011507751.1	Q9NZQ9-1
TMOD4	XM_047418672.1 link	c.485G>A	p.Ser162Asn	missense_variant, splice_region_variant	Exon 4 of 9		XP_047274628.1
TMOD4	XM_017001090.3 link	c.485G>A	p.Ser162Asn	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>A	p.Ser162Asn	missense_variant, splice_region_variant	Exon 5 of 10	1	NM_013353.3	ENSP00000295314.4		Q9NZQ9-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000531

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000438

AC:

AN:

251394

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.0000289

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:

0.0000137

AC:

AN:

1460484

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726644

show subpopulations

African (AFR)

AF:

0.000449

AC:

AN:

33442

American (AMR)

AF:

0.0000447

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:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111026

Other (OTH)

AF:

0.0000332

AC:

AN:

60320

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000144

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.000529

AC:

AN:

41558

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 12, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.485G>A (p.S162N) alteration is located in exon 5 (coding exon 4) of the TMOD4 gene. This alteration results from a G to A substitution at nucleotide position 485, causing the serine (S) at amino acid position 162 to be replaced by an asparagine (N). 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

0.11

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.048

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.12

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.82

M_CAP

Benign

0.0042

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.68

PhyloP100

5.0

PrimateAI

Uncertain

0.69

PROVEAN

Benign

0.61

REVEL

Benign

0.095

Sift

Benign

0.83

Sift4G

Benign

0.93

Polyphen

0.0

Vest4

0.13

MVP

0.54

MPC

0.24

ClinPred

0.038

GERP RS

5.7

PromoterAI

0.040

Neutral

(source)

Varity_R

0.12

gMVP

0.21

Mutation Taster

=51/49

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.035

dbscSNV1_RF

Benign

0.062

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over