14-59322935-C-T

Position:

• chr14-59322935-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001270520.2(DAAM1):​c.484C>T​(p.Leu162Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DAAM1 NM_001270520.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.86

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAAM1	NM_001270520.2	c.484C>T	p.Leu162Phe	missense_variant	6/25	ENST00000360909.8	NP_001257449.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAAM1	ENST00000360909.8	c.484C>T	p.Leu162Phe	missense_variant	6/25	1	NM_001270520.2	ENSP00000354162.3
DAAM1	ENST00000395125.1	c.484C>T	p.Leu162Phe	missense_variant	5/25	1		ENSP00000378557.1
DAAM1	ENST00000557327.1	n.440C>T		non_coding_transcript_exon_variant	3/3	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461734 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727160

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

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

Nov 21, 2024

The c.484C>T (p.L162F) alteration is located in exon 6 (coding exon 5) of the DAAM1 gene. This alteration results from a C to T substitution at nucleotide position 484, causing the leucine (L) at amino acid position 162 to be replaced by a phenylalanine (F). 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	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	2.9	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.7	D;D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.83
MutPred		0.65		Gain of catalytic residue at L158 (P = 0);Gain of catalytic residue at L158 (P = 0);
MVP		0.92
MPC		0.32
ClinPred		0.97	D
GERP RS		6.2
Varity_R		0.76
gMVP		0.55

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-59789653;