6-39901459-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001201427.2(DAAM2):c.2969G>A(p.Arg990His) variant causes a missense change. The variant allele was found at a frequency of 0.0000579 in 1,607,368 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R990L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAAM2	NM_001201427.2	c.2969G>A	p.Arg990His	missense_variant	24/25	ENST00000274867.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAAM2	ENST00000274867.9	c.2969G>A	p.Arg990His	missense_variant	24/25	1	NM_001201427.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152102 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000171 AC: 41 AN: 239776 Hom.: 0 AF XY: 0.000115 AC XY: 15 AN XY: 130622

Gnomad AFR exome AF: 0.0000665

Gnomad AMR exome AF: 0.000903

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000224

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000366

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000598 AC: 87 AN: 1455266 Hom.: 0 Cov.: 34 AF XY: 0.0000594 AC XY: 43 AN XY: 723874

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000873

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.0000207

Gnomad4 NFE exome AF: 0.0000342

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74310

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000113

ExAC AF: 0.0000662 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 12, 2022

The c.2969G>A (p.R990H) alteration is located in exon 24 (coding exon 23) of the DAAM2 gene. This alteration results from a G to A substitution at nucleotide position 2969, causing the arginine (R) at amino acid position 990 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	0.17
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.18	T;T;.;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
Sift4G	Uncertain	0.0090	D;D;D;D
Polyphen		1.0	.;D;.;D
Vest4		0.60
MutPred		0.28		.;Loss of MoRF binding (P = 0.0279);.;Loss of MoRF binding (P = 0.0279);
MVP		0.64
MPC		0.65
ClinPred		0.62	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.44

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; COSMIC: COSV51334935; COSMIC: COSV51334935;