chr6-39900206-A-C

Variant names:

• chr6-39900206-A-C
• rs553908697
• NM_001201427.2:c.2809A>C

Variant summary

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

The NM_001201427.2(DAAM2):​c.2809A>C​(p.Lys937Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. K937E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DAAM2 NM_001201427.2 missense, splice_region
• Scores: Splicing: ADA: 0.1550
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.29
• Publications: 0 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]

DAAM2-AS1 (HGNC:40830): (DAAM2 antisense RNA 1)

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.2809A>C	p.Lys937Gln	missense splice_region	Exon 23 of 25	NP_001188356.1	Q86T65-3
	DAAM2	NM_015345.4		c.2806A>C	p.Lys936Gln	missense splice_region	Exon 23 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.2809A>C	p.Lys937Gln	missense splice_region	Exon 23 of 25	ENSP00000274867.4	Q86T65-3
	DAAM2	ENST00000538976.5	TSL:1	c.2806A>C	p.Lys936Gln	missense splice_region	Exon 23 of 25	ENSP00000437808.1	Q86T65-4
	DAAM2	ENST00000631498.1	TSL:1	n.3504A>C		splice_region non_coding_transcript_exon	Exon 7 of 9

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457528 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724636

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33302

American (AMR) AF: 0.00 AC: 0 AN: 44390

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26004

East Asian (EAS) AF: 0.00 AC: 0 AN: 39430

South Asian (SAS) AF: 0.00 AC: 0 AN: 85078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110242

Other (OTH) AF: 0.00 AC: 0 AN: 60234

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.44	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.11
Sift	Benign	0.13	T
Sift4G	Benign	0.40	T
Polyphen		1.0	D
Vest4		0.55
MutPred		0.53		Loss of ubiquitination at K937 (P = 0.0233)
MVP		0.32
MPC		0.62
ClinPred		0.81	D
GERP RS		5.1
Varity_R		0.35
gMVP		0.54
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.16
dbscSNV1_RF	Benign	0.39
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: rs553908697; hg19: chr6-39867982;