20-17607039-A-G

Position:

• chr20-17607039-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006870.4(DSTN):​c.391A>G​(p.Ile131Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 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.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DSTN NM_006870.4 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSTN	NM_006870.4	c.391A>G	p.Ile131Val	missense_variant, splice_region_variant	4/4	ENST00000246069.12	NP_006861.1
DSTN	NM_001011546.2	c.340A>G	p.Ile114Val	missense_variant, splice_region_variant	5/5		NP_001011546.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSTN	ENST00000246069.12	c.391A>G	p.Ile131Val	missense_variant, splice_region_variant	4/4	1	NM_006870.4	ENSP00000246069.6
DSTN	ENST00000474024.5	c.340A>G	p.Ile114Val	missense_variant, splice_region_variant	5/5	1		ENSP00000476975.1
DSTN	ENST00000449141.2	n.*85A>G		splice_region_variant, non_coding_transcript_exon_variant	5/5	3		ENSP00000434355.1
DSTN	ENST00000449141.2	n.*85A>G		3_prime_UTR_variant	5/5	3		ENSP00000434355.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461416 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726976

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 02, 2024

The c.391A>G (p.I131V) alteration is located in exon 4 (coding exon 4) of the DSTN gene. This alteration results from a A to G substitution at nucleotide position 391, causing the isoleucine (I) at amino acid position 131 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0084	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.59	N;.
REVEL	Benign	0.22
Sift	Benign	0.25	T;.
Sift4G	Benign	0.19	T;T
Polyphen		0.14	B;.
Vest4		0.41
MutPred		0.79		Gain of methylation at K132 (P = 0.0739);.;
MVP		0.45
MPC		0.76
ClinPred		0.89	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.40

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

LitVar

Other links and lift over

dbSNP: rs2035650349; hg19: chr20-17587684;