rs1555874726
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP2PP5_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
NM_015330.6 missense
Scores
12
3
1
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;D
Vest4
MutPred
Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;
MVP
MPC
1.3
ClinPred
D
GERP RS
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at