rs191511427

Variant names:

• chr12-105107849-G-A
• rs191511427
• NM_015275.3:c.49G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-105107849-G-A
• chr12-105107849-G-C
• chr12-105107849-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_015275.3(WASHC4):​c.49G>A​(p.Asp17Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00026 in 1,550,470 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D17E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: WASHC4 NM_015275.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 5.79
• Publications: 1 publications found

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]

ALDH1L2 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LOC414300 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008968204).
• BP6: Variant 12-105107849-G-A is Benign according to our data. Variant chr12-105107849-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 742318.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00145 (221/152304) while in subpopulation AFR AF = 0.00498 (207/41566). AF 95% confidence interval is 0.00442. There are 0 homozygotes in GnomAd4. There are 103 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015275.3. 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
	WASHC4	NM_015275.3	MANE Select	c.49G>A	p.Asp17Asn	missense	Exon 1 of 33	NP_056090.1	Q2M389-1
	WASHC4	NM_001293640.2		c.49G>A	p.Asp17Asn	missense	Exon 1 of 33	NP_001280569.1	A0A087X256
	LOC414300	NR_121211.1		n.-207C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WASHC4	ENST00000332180.10	TSL:1 MANE Select	c.49G>A	p.Asp17Asn	missense	Exon 1 of 33	ENSP00000328062.6	Q2M389-1
	WASHC4	ENST00000620430.5	TSL:1	c.49G>A	p.Asp17Asn	missense	Exon 1 of 33	ENSP00000484713.1	A0A087X256
	WASHC4	ENST00000934676.1		c.49G>A	p.Asp17Asn	missense	Exon 1 of 33	ENSP00000604735.1

Frequencies

GnomAD3 genomes AF: 0.00143 AC: 218 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00492

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

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: 0.00143

GnomAD2 exomes AF: 0.000255 AC: 39 AN: 153222 AF XY: 0.000197

Gnomad AFR exome AF: 0.00356

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.000231

GnomAD4 exome AF: 0.000130 AC: 182 AN: 1398166 Hom.: 1 Cov.: 29 AF XY: 0.000119 AC XY: 82 AN XY: 689728

African (AFR) AF: 0.00450 AC: 142 AN: 31566

American (AMR) AF: 0.000308 AC: 11 AN: 35694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49070

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5692

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1078106

Other (OTH) AF: 0.000345 AC: 20 AN: 57942

GnomAD4 genome AF: 0.00145 AC: 221 AN: 152304 Hom.: 0 Cov.: 32 AF XY: 0.00138 AC XY: 103 AN XY: 74488

African (AFR) AF: 0.00498 AC: 207 AN: 41566

American (AMR) AF: 0.000718 AC: 11 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000542 Hom.: 0

Bravo AF: 0.00153

ESP6500AA AF: 0.00102 AC: 4

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000155 AC: 10

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Intellectual disability, autosomal recessive 43 (1)
-	-	1	not provided (1)
-	-	1	WASHC4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.14
Sift	Benign	0.14	T
Sift4G	Benign	0.12	T
Polyphen		0.73	P
Vest4		0.43
MVP		0.58
MPC		0.54
ClinPred		0.087	T
GERP RS		4.1
PromoterAI		-0.11	Neutral
Varity_R		0.50
gMVP		0.57
Mutation Taster		=88/12	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: rs191511427; hg19: chr12-105501627;