14-59326535-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001270520.2(DAAM1):c.1200G>T(p.Gln400His) variant causes a missense change. The variant allele was found at a frequency of 0.0000291 in 1,612,412 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: DAAM1 NM_001270520.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23818535).
• BS2: High AC in GnomAd at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAAM1	NM_001270520.2	c.1200G>T	p.Gln400His	missense_variant	11/25	ENST00000360909.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAAM1	ENST00000360909.8	c.1200G>T	p.Gln400His	missense_variant	11/25	1	NM_001270520.2	P1
DAAM1	ENST00000395125.1	c.1200G>T	p.Gln400His	missense_variant	10/25	1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 151900 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000532

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

GnomAD3 exomes AF: 0.0000479 AC: 12 AN: 250322 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135336

Gnomad AFR exome AF: 0.000680

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.0000171 AC: 25 AN: 1460512 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726464

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.000145 AC: 22 AN: 151900 Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74154

Gnomad4 AFR AF: 0.000532

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

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

Jan 23, 2024

The c.1200G>T (p.Q400H) alteration is located in exon 11 (coding exon 10) of the DAAM1 gene. This alteration results from a G to T substitution at nucleotide position 1200, causing the glutamine (Q) at amino acid position 400 to be replaced by a histidine (H). 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	0.27
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Pathogenic	0.22
Cadd	Benign	21
Dann	Uncertain	0.98
Eigen	Benign	0.089
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Uncertain	0.49
Sift	Benign	0.15	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0010	B;B
Vest4		0.46
MutPred		0.55		Gain of catalytic residue at L404 (P = 0.0019);Gain of catalytic residue at L404 (P = 0.0019);
MVP		0.96
MPC		0.28
ClinPred		0.080	T
GERP RS		5.1
Varity_R		0.27
gMVP		0.54

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: rs139756687; hg19: chr14-59793253;