Genetic Variant DSTN:p.Ile131Leu (chr20-17607039-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006870.4(DSTN):c.391A>C(p.Ile131Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,416 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 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. I131V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DSTN
NM_006870.4 missense, splice_region

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.03

Publications

0 publications found

Variant links:

Genes affected

DSTN (HGNC:15750): (destrin, actin depolymerizing factor) The product of this gene belongs to the actin-binding proteins ADF family. This family of proteins is responsible for enhancing the turnover rate of actin in vivo. This gene encodes the actin depolymerizing protein that severs actin filaments (F-actin) and binds to actin monomers (G-actin). Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

DSTN links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006870.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSTN	NM_006870.4	MANE Select	c.391A>C	p.Ile131Leu	missense splice_region	Exon 4 of 4	NP_006861.1	P60981-1
	DSTN	NM_001011546.2		c.340A>C	p.Ile114Leu	missense splice_region	Exon 5 of 5	NP_001011546.1	P60981-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSTN	ENST00000246069.12	TSL:1 MANE Select	c.391A>C	p.Ile131Leu	missense splice_region	Exon 4 of 4	ENSP00000246069.6	P60981-1
DSTN	ENST00000474024.5	TSL:1	c.340A>C	p.Ile114Leu	missense splice_region	Exon 5 of 5	ENSP00000476975.1	P60981-2
DSTN	ENST00000925115.1		c.391A>C	p.Ile131Leu	missense splice_region	Exon 5 of 5	ENSP00000595174.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461416

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33460

American (AMR)

AF:

0.00

AC:

AN:

44652

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.00

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111868

Other (OTH)

AF:

0.00

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.65

BayesDel_addAF

Uncertain

0.015

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.82

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.3

PhyloP100

8.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.3

REVEL

Benign

0.21

Sift

Benign

0.14

Sift4G

Benign

0.099

Polyphen

0.091

Vest4

0.55

MutPred

0.82

Loss of methylation at K127 (P = 0.0554)

MVP

0.54

MPC

1.2

ClinPred

0.93

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.54

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over