2-19951450-T-G

Variant names:

• chr2-19951450-T-G
• rs797046099
• NM_001006657.2:c.1468A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_020779.4(WDR35):​c.1435A>C​(p.Met479Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict 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. M479V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: WDR35 NM_020779.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.02
• Publications: 1 publications found

Genes affected

WDR35 (HGNC:29250): (WD repeat domain 35) This gene encodes a member of the WD repeat protein family. WD repeats are minimally conserved regions of approximately 40 amino acids typically bracketed by gly-his and trp-asp (GH-WD), which may facilitate formation of heterotrimeric or multiprotein complexes. Members of this family are involved in a variety of cellular processes, including cell cycle progression, signal transduction, apoptosis, and gene regulation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. Two patients with Sensenbrenner syndrome / cranioectodermal dysplasia (CED) were identified with mutations in this gene, consistent with a possible ciliary function.[provided by RefSeq, Sep 2010]

WDR35 Gene-Disease associations (from GenCC):

• cranioectodermal dysplasia 2

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, G2P, Ambry Genetics
• short-rib thoracic dysplasia 7 with or without polydactyly

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• cranioectodermal dysplasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• short rib-polydactyly syndrome, Verma-Naumoff type

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047182113).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020779.4. 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
	WDR35	NM_001006657.2	MANE Plus Clinical	c.1468A>C	p.Met490Leu	missense	Exon 14 of 28	NP_001006658.1	Q9P2L0-1
	WDR35	NM_020779.4	MANE Select	c.1435A>C	p.Met479Leu	missense	Exon 13 of 27	NP_065830.2	Q9P2L0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WDR35	ENST00000345530.8	TSL:1 MANE Plus Clinical	c.1468A>C	p.Met490Leu	missense	Exon 14 of 28	ENSP00000314444.5	Q9P2L0-1
	WDR35	ENST00000281405.9	TSL:1 MANE Select	c.1435A>C	p.Met479Leu	missense	Exon 13 of 27	ENSP00000281405.5	Q9P2L0-2
	WDR35	ENST00000453014.1	TSL:1	c.73A>C	p.Met25Leu	missense	Exon 2 of 10	ENSP00000404409.1	H0Y6C0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.43
DEOGEN2	Benign	0.0096	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.0
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.26
Sift	Benign	0.79	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.068
MutPred		0.21		Gain of glycosylation at S489 (P = 0.0449)
MVP		0.38
MPC		0.10
ClinPred		0.0091	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.065
gMVP		0.12
Mutation Taster		=92/8	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: rs797046099; hg19: chr2-20151211;