6-39867596-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001201427.2(DAAM2):c.515G>A(p.Arg172His) variant causes a missense change. The variant allele was found at a frequency of 0.00301 in 1,613,992 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R172C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0031 (18 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.22

Genes affected

DAAM2 (HGNC:18143): (dishevelled associated activator of morphogenesis 2) Predicted to enable actin binding activity and small GTPase binding activity. Predicted to be involved in nervous system development and regulation of Wnt signaling pathway. Predicted to act upstream of or within determination of left/right symmetry. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011351585).
• BP6: Variant 6-39867596-G-A is Benign according to our data. Variant chr6-39867596-G-A is described in ClinVar as [Benign]. Clinvar id is 3039245.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAAM2	NM_001201427.2	c.515G>A	p.Arg172His	missense_variant	6/25	ENST00000274867.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAAM2	ENST00000274867.9	c.515G>A	p.Arg172His	missense_variant	6/25	1	NM_001201427.2	P1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152162 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0124

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00262

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00204 AC: 507 AN: 249104 Hom.: 4 AF XY: 0.00212 AC XY: 286 AN XY: 135158

Gnomad AFR exome AF: 0.000258

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000928

Gnomad NFE exome AF: 0.00283

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00312 AC: 4561 AN: 1461710 Hom.: 18 Cov.: 31 AF XY: 0.00303 AC XY: 2201 AN XY: 727138

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00353

Gnomad4 OTH exome AF: 0.00366

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.00188 AC XY: 140 AN XY: 74470

Gnomad4 AFR AF: 0.000481

Gnomad4 AMR AF: 0.00281

Gnomad4 ASJ AF: 0.0124

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00260

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00305 Hom.: 3

Bravo AF: 0.00241

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00247 AC: 21

ExAC AF: 0.00185 AC: 224

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DAAM2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.10	T;D;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.97	D;.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.011	T;T;T;T
MetaSVM	Uncertain	0.18	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.98	.;D;.;D
Vest4		0.42
MVP		0.73
MPC		0.70
ClinPred		0.32	T
GERP RS		4.5
Varity_R		0.15
gMVP		0.50

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: rs200589550; hg19: chr6-39835372; COSMIC: COSV51306116; COSMIC: COSV51306116;