6-39901459-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_001201427.2(DAAM2):c.2969G>T(p.Arg990Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00196 in 1,607,480 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R990H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 6.62

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]

MOCS1 (HGNC:7190): (molybdenum cofactor synthesis 1) Molybdenum cofactor biosynthesis is a conserved pathway leading to the biological activation of molybdenum. The protein encoded by this gene is involved in this pathway. This gene was originally thought to produce a bicistronic mRNA with the potential to produce two proteins (MOCS1A and MOCS1B) from adjacent open reading frames. However, only the first open reading frame (MOCS1A) has been found to encode a protein from the putative bicistronic mRNA, whereas additional splice variants are likely to produce a fusion between the two open reading frames. This gene is defective in patients with molybdenum cofactor deficiency, type A. A related pseudogene has been identified on chromosome 16. [provided by RefSeq, Nov 2017]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016001016).
• BP6: Variant 6-39901459-G-T is Benign according to our data. Variant chr6-39901459-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3044638.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAAM2	NM_001201427.2	c.2969G>T	p.Arg990Leu	missense_variant	24/25	ENST00000274867.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAAM2	ENST00000274867.9	c.2969G>T	p.Arg990Leu	missense_variant	24/25	1	NM_001201427.2	P1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152100 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00199

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00147 AC: 353 AN: 239776 Hom.: 0 AF XY: 0.00152 AC XY: 198 AN XY: 130622

Gnomad AFR exome AF: 0.000266

Gnomad AMR exome AF: 0.00172

Gnomad ASJ exome AF: 0.00501

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00142

Gnomad FIN exome AF: 0.000116

Gnomad NFE exome AF: 0.00175

Gnomad OTH exome AF: 0.000843

GnomAD4 exome AF: 0.00202 AC: 2933 AN: 1455262 Hom.: 6 Cov.: 34 AF XY: 0.00193 AC XY: 1400 AN XY: 723874

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00172

Gnomad4 ASJ exome AF: 0.00545

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.000186

Gnomad4 NFE exome AF: 0.00219

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152218 Hom.: 1 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74436

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00199

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00155

ESP6500AA AF: 0.000245 AC: 1

ESP6500EA AF: 0.00311 AC: 26

ExAC AF: 0.00118 AC: 143

EpiCase AF: 0.00224

EpiControl AF: 0.00196

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

DAAM2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2022

This variant is classified as likely 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;.;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;.;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.79	T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.068	.;B;.;B
Vest4		0.60
MVP		0.57
MPC		0.60
ClinPred		0.041	T
GERP RS		5.2
Varity_R		0.39
gMVP		0.62

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: rs199589116; hg19: chr6-39869235;