NM_001201427.2:c.220C>A

Variant names:

• chr6-39860979-C-A
• rs370112679
• NM_001201427.2:c.220C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001201427.2(DAAM2):​c.220C>A​(p.Pro74Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000589 in 1,613,048 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000056 (1 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 2.47

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024380147).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAAM2	NM_001201427.2	c.220C>A	p.Pro74Thr	missense_variant	Exon 3 of 25	ENST00000274867.9	NP_001188356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAAM2	ENST00000274867.9	c.220C>A	p.Pro74Thr	missense_variant	Exon 3 of 25	1	NM_001201427.2	ENSP00000274867.4

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152080 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.00146

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000848 AC: 21 AN: 247640 Hom.: 0 AF XY: 0.0000819 AC XY: 11 AN XY: 134244

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000726

Gnomad SAS exome AF: 0.000199

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1460850 Hom.: 1 Cov.: 31 AF XY: 0.0000537 AC XY: 39 AN XY: 726580

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.000597

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152198 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74420

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000968

Gnomad4 SAS AF: 0.00146

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

ExAC AF: 0.0000745 AC: 9

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

DAAM2-related disorder Uncertain:1

Feb 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DAAM2 c.220C>A variant is predicted to result in the amino acid substitution p.Pro74Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.073% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Nephrotic syndrome, type 24 Uncertain:1

Feb 01, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.058	T;T;.;T;D
Eigen	Benign	-0.029
Eigen_PC	Benign	0.028
FATHMM_MKL	Benign	0.67	D
LIST_S2	Uncertain	0.88	D;.;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.024	T;T;T;T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.8	.;L;L;L;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-2.1	.;N;N;N;D
REVEL	Benign	0.27
Sift	Benign	0.20	.;T;T;T;D
Sift4G	Benign	0.33	T;T;T;T;D
Polyphen		0.080, 0.98	.;B;.;B;D
Vest4		0.38
MutPred		0.54		Loss of catalytic residue at P73 (P = 0.0121);Loss of catalytic residue at P73 (P = 0.0121);Loss of catalytic residue at P73 (P = 0.0121);Loss of catalytic residue at P73 (P = 0.0121);Loss of catalytic residue at P73 (P = 0.0121);
MVP		0.68
MPC		0.24
ClinPred		0.042	T
GERP RS		5.3
Varity_R		0.12
gMVP		0.58

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: rs370112679; hg19: chr6-39828755;