14-59320544-A-G

Position:

chr14-59320544-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_001270520.2(DAAM1):c.400A>G(p.Ile134Val) variant causes a missense change. The variant allele was found at a frequency of 0.000896 in 1,606,180 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00078 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 2 hom. )

Consequence

DAAM1
NM_001270520.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.03

Variant links:

Genes affected

DAAM1 (HGNC:18142): (dishevelled associated activator of morphogenesis 1) Cell motility, adhesion, cytokinesis, and other functions of the cell cortex are mediated by reorganization of the actin cytoskeleton and several formin homology (FH) proteins have been associated with these processes. The protein encoded by this gene contains two FH domains and belongs to a novel FH protein subfamily implicated in cell polarity. A key regulator of cytoskeletal architecture, the small GTPase Rho, is activated during development by Wnt/Fz signaling to control cell polarity and movement. The protein encoded by this gene is thought to function as a scaffolding protein for the Wnt-induced assembly of a disheveled (Dvl)-Rho complex. This protein also promotes the nucleation and elongation of new actin filaments and regulates cell growth through the stabilization of microtubules. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jul 2012]

DAAM1 links:

DAAM1 (HGNC:):

DAAM1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027221113).

BP6

Variant 14-59320544-A-G is Benign according to our data. Variant chr14-59320544-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 983072.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High AC in GnomAd4 at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAAM1	NM_001270520.2 linkuse as main transcript	c.400A>G	p.Ile134Val	missense_variant	5/25	ENST00000360909.8	NP_001257449.1	Q9Y4D1-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DAAM1	ENST00000360909.8 linkuse as main transcript	c.400A>G	p.Ile134Val	missense_variant	5/25	1	NM_001270520.2	ENSP00000354162.3	Q9Y4D1-2
DAAM1	ENST00000395125.1 linkuse as main transcript	c.400A>G	p.Ile134Val	missense_variant	4/25	1		ENSP00000378557.1	Q9Y4D1-1
DAAM1	ENST00000557327.1 linkuse as main transcript	n.356A>G		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes

AF:

0.000777

AC:

118

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000918

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000667

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00127

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000637

AC:

155

AN:

243352

Hom.:

AF XY:

0.000684

AC XY:

AN XY:

131660

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000185

Gnomad ASJ exome

AF:

0.000811

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000746

Gnomad NFE exome

AF:

0.00105

Gnomad OTH exome

AF:

0.00102

GnomAD4 exome

AF:

0.000908

AC:

1321

AN:

1454152

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

619

AN XY:

723218

show subpopulations

Gnomad4 AFR exome

AF:

0.000183

Gnomad4 AMR exome

AF:

0.000233

Gnomad4 ASJ exome

AF:

0.000616

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.000806

Gnomad4 NFE exome

AF:

0.00109

Gnomad4 OTH exome

AF:

0.000549

GnomAD4 genome

AF:

0.000776

AC:

118

AN:

152028

Hom.:

Cov.:

AF XY:

0.000605

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000667

Gnomad4 NFE

AF:

0.00127

Gnomad4 OTH

AF:

0.000475

Alfa

AF:

0.00114

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000750

AC:

EpiCase

AF:

0.000936

EpiControl

AF:

0.000540

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 29, 2023

The c.400A>G (p.I134V) alteration is located in exon 5 (coding exon 4) of the DAAM1 gene. This alteration results from a A to G substitution at nucleotide position 400, causing the isoleucine (I) at amino acid position 134 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Seizure

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.28

.;T

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.063

MetaRNN

Benign

0.027

T;T

MetaSVM

Uncertain

0.042

MutationAssessor

Benign

-0.68

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

0.060

N;N

REVEL

Uncertain

0.49

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.65

P;P

Vest4

0.15

MVP

0.49

MPC

0.25

ClinPred

0.10

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.20

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over