6-39901450-G-C

Variant names:

• chr6-39901450-G-C
• rs375987274
• NM_001201427.2:c.2960G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001201427.2(DAAM2):​c.2960G>C​(p.Arg987Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,948 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R987W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DAAM2 NM_001201427.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.71
• Publications: 2 publications found

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]

MOCS1 Gene-Disease associations (from GenCC):

• sulfite oxidase deficiency due to molybdenum cofactor deficiency type A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001201427.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAAM2	NM_001201427.2	MANE Select	c.2960G>C	p.Arg987Pro	missense	Exon 24 of 25	NP_001188356.1	Q86T65-3
	DAAM2	NM_015345.4		c.2957G>C	p.Arg986Pro	missense	Exon 24 of 25	NP_056160.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAAM2	ENST00000274867.9	TSL:1 MANE Select	c.2960G>C	p.Arg987Pro	missense	Exon 24 of 25	ENSP00000274867.4	Q86T65-3
	DAAM2	ENST00000538976.5	TSL:1	c.2957G>C	p.Arg986Pro	missense	Exon 24 of 25	ENSP00000437808.1	Q86T65-4
	DAAM2	ENST00000631498.1	TSL:1	n.3655G>C		non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 243756 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457948 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725294

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50134

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111702

Other (OTH) AF: 0.0000166 AC: 1 AN: 60312

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000384 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	-0.074	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		6.7
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.66
MutPred		0.40		Loss of MoRF binding (P = 0.0024)
MVP		0.48
MPC		0.72
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.89
gMVP		0.83
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

dbSNP: rs375987274; hg19: chr6-39869226;