rs387907108
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP2PP5
The NM_015330.6(SPECC1L):c.1244A>C(p.Gln415Pro) 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 (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
SPECC1L
NM_015330.6 missense
NM_015330.6 missense
Scores
7
7
3
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 6 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 22-24322224-A-C is Pathogenic according to our data. Variant chr22-24322224-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 31101.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-24322224-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.1244A>C | p.Gln415Pro | missense_variant | 5/17 | ENST00000314328.14 | NP_056145.5 | |
SPECC1L | NM_001145468.4 | c.1244A>C | p.Gln415Pro | missense_variant | 4/16 | NP_001138940.4 | ||
SPECC1L | NM_001254732.3 | c.1244A>C | p.Gln415Pro | missense_variant | 4/15 | NP_001241661.3 | ||
SPECC1L-ADORA2A | NR_103546.1 | n.1552A>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.1244A>C | p.Gln415Pro | missense_variant | 5/17 | 1 | NM_015330.6 | ENSP00000325785.8 | ||
SPECC1L-ADORA2A | ENST00000358654.2 | n.1244A>C | non_coding_transcript_exon_variant | 5/20 | 2 | ENSP00000351480.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Oculomaxillofacial dysostosis Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 2011 | - - |
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
Pathogenic
.;D;.;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;T;D;D
Vest4
MutPred
Gain of glycosylation at Q415 (P = 0.0306);Gain of glycosylation at Q415 (P = 0.0306);Gain of glycosylation at Q415 (P = 0.0306);Gain of glycosylation at Q415 (P = 0.0306);
MVP
MPC
1.3
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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