6-39865007-G-A

Variant names:

• chr6-39865007-G-A
• rs1391253919
• NM_001201427.2:c.361G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001201427.2(DAAM2):​c.361G>A​(p.Glu121Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E121Q) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.42

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-39865007-G-C is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.39811808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DAAM2	NM_001201427.2	c.361G>A	p.Glu121Lys	missense_variant	Exon 5 of 25	ENST00000274867.9	NP_001188356.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DAAM2	ENST00000274867.9	c.361G>A	p.Glu121Lys	missense_variant	Exon 5 of 25	1	NM_001201427.2	ENSP00000274867.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74362

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.080	T;T;.;T
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;.;D;D
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.40	T;T;T;T
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	2.0	.;M;M;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	.;N;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.039	.;D;D;D
Sift4G	Uncertain	0.022	D;D;D;D
Polyphen		0.86	.;P;.;P
Vest4		0.41
MutPred		0.59		Gain of ubiquitination at E121 (P = 0.0128);Gain of ubiquitination at E121 (P = 0.0128);Gain of ubiquitination at E121 (P = 0.0128);Gain of ubiquitination at E121 (P = 0.0128);
MVP		0.48
MPC		0.17
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.34
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1391253919; hg19: chr6-39832783;