chr12-105107859-A-G

Variant names:

• chr12-105107859-A-G
• NM_015275.3:c.59A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015275.3(WASHC4):​c.59A>G​(p.Gln20Arg) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: WASHC4 NM_015275.3 missense, splice_region
• Scores: Splicing: ADA: 0.3016
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

Genes affected

WASHC4 (HGNC:29174): (WASH complex subunit 4) This gene encodes a component of the WASH complex, which functions in the intracellular transport of endosomes. Mutations in this gene have been detected in individuals with autosomal recessive cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ALDH1L2 (HGNC:26777): (aldehyde dehydrogenase 1 family member L2) This gene encodes a member of both the aldehyde dehydrogenase superfamily and the formyl transferase superfamily. This member is the mitochondrial form of 10-formyltetrahydrofolate dehydrogenase (FDH), which converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in an NADP(+)-dependent reaction, and plays an essential role in the distribution of one-carbon groups between the cytosolic and mitochondrial compartments of the cell. Alternatively spliced transcript variants have been found for this gene.[provided by RefSeq, Oct 2010]

LOC414300 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10362241).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WASHC4	NM_015275.3	c.59A>G	p.Gln20Arg	missense_variant, splice_region_variant	Exon 1 of 33	ENST00000332180.10	NP_056090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WASHC4	ENST00000332180.10	c.59A>G	p.Gln20Arg	missense_variant, splice_region_variant	Exon 1 of 33	1	NM_015275.3	ENSP00000328062.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59A>G (p.Q20R) alteration is located in exon 1 (coding exon 1) of the KIAA1033 gene. This alteration results from a A to G substitution at nucleotide position 59, causing the glutamine (Q) at amino acid position 20 to be replaced by an arginine (R). 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	0.16
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.0042	T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.036
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.72	N;.
REVEL	Benign	0.069
Sift	Benign	0.52	T;.
Sift4G	Benign	0.68	T;T
Polyphen		0.0020	B;.
Vest4		0.14
MutPred		0.23		Gain of catalytic residue at E25 (P = 0.0148);Gain of catalytic residue at E25 (P = 0.0148);
MVP		0.31
MPC		0.19
ClinPred		0.70	D
GERP RS		3.9
Varity_R		0.31
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.30
dbscSNV1_RF	Benign	0.46
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-105501637;