6-39864488-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001201427.2(DAAM2):c.314G>A(p.Arg105His) variant causes a missense change. The variant allele was found at a frequency of 0.00118 in 1,611,824 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R105C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0046 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00082 (7 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.29

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0097029805).
• BP6: Variant 6-39864488-G-A is Benign according to our data. Variant chr6-39864488-G-A is described in ClinVar as [Benign]. Clinvar id is 3039055.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000819 (1195/1459632) while in subpopulation AFR AF= 0.0168 (563/33424). AF 95% confidence interval is 0.0157. There are 7 homozygotes in gnomad4_exome. There are 569 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAAM2	NM_001201427.2	c.314G>A	p.Arg105His	missense_variant	4/25	ENST00000274867.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAAM2	ENST00000274867.9	c.314G>A	p.Arg105His	missense_variant	4/25	1	NM_001201427.2	P1

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152074 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00255

Gnomad ASJ AF: 0.00922

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00172 AC: 425 AN: 246724 Hom.: 1 AF XY: 0.00135 AC XY: 180 AN XY: 133800

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.0100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000664

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000241

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.000819 AC: 1195 AN: 1459632 Hom.: 7 Cov.: 31 AF XY: 0.000784 AC XY: 569 AN XY: 725962

Gnomad4 AFR exome AF: 0.0168

Gnomad4 AMR exome AF: 0.00188

Gnomad4 ASJ exome AF: 0.00931

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00462 AC: 703 AN: 152192 Hom.: 5 Cov.: 32 AF XY: 0.00430 AC XY: 320 AN XY: 74408

Gnomad4 AFR AF: 0.0146

Gnomad4 AMR AF: 0.00255

Gnomad4 ASJ AF: 0.00922

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00135 Hom.: 2

Bravo AF: 0.00524

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0125 AC: 50

ESP6500EA AF: 0.000838 AC: 7

ExAC AF: 0.00169 AC: 205

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000238

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

May 24, 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	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;D;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;.;D;D
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Uncertain	0.53	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.44	T
Sift4G	Uncertain	0.023	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.52
MVP		0.74
MPC		0.72
ClinPred		0.034	T
GERP RS		5.9
Varity_R		0.35
gMVP		0.61

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: rs6919807; hg19: chr6-39832264; COSMIC: COSV99224783; COSMIC: COSV99224783;