rs1555874726

Positions:

• chr22-24414562-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP2 PP5_Very_Strong

The NM_015330.6(SPECC1L):​c.3293G>A​(p.Arg1098Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPECC1L NM_015330.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.77

Genes affected

SPECC1L (HGNC:29022): (sperm antigen with calponin homology and coiled-coil domains 1 like) This gene encodes a coiled-coil domain containing protein. The encoded protein may play a critical role in actin-cytoskeletal reorganization during facial morphogenesis. Mutations in this gene are a cause of oblique facial clefting-1. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A read-through transcript composed of SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and the downstream ADORA2A (adenosine A2a receptor) gene sequence has been identified, but it is thought to be non-coding. [provided by RefSeq, Jun 2013]

SPECC1L-ADORA2A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SPECC1L
• PP5: Variant 22-24414562-G-A is Pathogenic according to our data. Variant chr22-24414562-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 445948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPECC1L	NM_015330.6	c.3293G>A	p.Arg1098Gln	missense_variant	17/17	ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1	n.3723G>A		non_coding_transcript_exon_variant	18/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14	c.3293G>A	p.Arg1098Gln	missense_variant	17/17	1	NM_015330.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Teebi hypertelorism syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Dept of Genetics, Assistance Publique-Hôpitaux de Paris (APHP) - R DEBRE University Hospital

Jun 01, 2018

- -

Teebi hypertelorism syndrome 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 06, 2022

- -

SPECC1L-related syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Aug 21, 2020

The SPECC1L c.3293G>A (p.Arg1098Gln) variant is a missense variant. The p.Arg1098Gln variant has been reported in one study in which it was identified in a heterozygous state in four individuals from a three generation family and in a heterozygous de novo state in one additional unrelated individual, all affected with SPECC1L-related disorders (Bhoj et al. 2019). The variant is in the calponin-homology domain of the protein, a domain involved in actin-binding. The p.Arg1098Gln variant is not found in the Genome Aggregation Database and is in a region of good sequence coverage, so the variant is presumed to be rare. Pathogenicity of the variant is supported by in silico prediction data. The substitution of arginine for glutamine at this position represents a change in charge. Based on the collective evidence, the p.Arg1098Gln variant is classified as pathogenic for SPECC1L-related syndrome. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Vest4		0.84
MutPred		0.32		Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555874726; hg19: chr22-24810530;