rs786201030
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP5_Moderate
The NM_015330.6(SPECC1L):c.1189A>C(p.Thr397Pro) 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
6
9
2
Clinical Significance
Conservation
PhyloP100: 9.12
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:49185): (SPECC1L-ADORA2A readthrough (NMD candidate)) This locus represents naturally occurring readthrough transcription between the neighboring SPECC1L (sperm antigen with calponin homology and coiled-coil domains 1-like) and ADORA2A (adenosine A2a receptor) genes on chromosome 22. The readthrough transcript is a candidate for nonsense-mediated mRNA decay (NMD) and is unlikely to produce a protein product. [provided by RefSeq, Jun 2013]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a coiled_coil_region (size 55) in uniprot entity CYTSA_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_015330.6
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPECC1L. . Gene score misZ 1.5985 (greater than the threshold 3.09). Trascript score misZ 3.1934 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant Opitz G/BBB syndrome, hypertelorism, Teebi type, commissural facial cleft, Tessier number 4 facial cleft.
PP5
Variant 22-24322169-A-C is Pathogenic according to our data. Variant chr22-24322169-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 183671.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-24322169-A-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
SPECC1L | NM_015330.6 | c.1189A>C | p.Thr397Pro | missense_variant | 5/17 | ENST00000314328.14 | NP_056145.5 | |
SPECC1L | NM_001145468.4 | c.1189A>C | p.Thr397Pro | missense_variant | 4/16 | NP_001138940.4 | ||
SPECC1L | NM_001254732.3 | c.1189A>C | p.Thr397Pro | missense_variant | 4/15 | NP_001241661.3 | ||
SPECC1L-ADORA2A | NR_103546.1 | n.1497A>C | non_coding_transcript_exon_variant | 5/20 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
SPECC1L | ENST00000314328.14 | c.1189A>C | p.Thr397Pro | missense_variant | 5/17 | 1 | NM_015330.6 | ENSP00000325785.8 | ||
SPECC1L-ADORA2A | ENST00000358654.2 | n.1189A>C | non_coding_transcript_exon_variant | 5/20 | 2 | ENSP00000351480.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
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 | Feb 01, 2015 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2023 | For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SPECC1L function (PMID: 25412741). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 183671). This missense change has been observed in individual(s) with clinical features of SPECC1L-related disorders (PMID: 25412741, 30472488). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 397 of the SPECC1L protein (p.Thr397Pro). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;.;.
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Vest4
MutPred
Loss of catalytic residue at T397 (P = 0.075);Loss of catalytic residue at T397 (P = 0.075);Loss of catalytic residue at T397 (P = 0.075);Loss of catalytic residue at T397 (P = 0.075);
MVP
MPC
1.4
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