rs387907108

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

Scores

7
7
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.12
Variant links:
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]

Genome browser will be placed here

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
SPECC1LNM_015330.6 linkuse as main transcriptc.1244A>C p.Gln415Pro missense_variant 5/17 ENST00000314328.14 NP_056145.5 Q69YQ0-1B2RMV2
SPECC1LNM_001145468.4 linkuse as main transcriptc.1244A>C p.Gln415Pro missense_variant 4/16 NP_001138940.4 B2RMV2
SPECC1LNM_001254732.3 linkuse as main transcriptc.1244A>C p.Gln415Pro missense_variant 4/15 NP_001241661.3 Q69YQ0-2
SPECC1L-ADORA2ANR_103546.1 linkuse as main transcriptn.1552A>C non_coding_transcript_exon_variant 5/20

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPECC1LENST00000314328.14 linkuse as main transcriptc.1244A>C p.Gln415Pro missense_variant 5/171 NM_015330.6 ENSP00000325785.8 Q69YQ0-1
SPECC1L-ADORA2AENST00000358654.2 linkuse as main transcriptn.1244A>C non_coding_transcript_exon_variant 5/202 ENSP00000351480.2 F8WAN1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
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 providedliterature onlyOMIMJul 15, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
29
DANN
Uncertain
1.0
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
.;D;.;.
M_CAP
Benign
0.084
D
MetaRNN
Uncertain
0.70
D;D;D;D
MetaSVM
Benign
-1.1
T
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.7
D;D;D;D
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D;D;D;D
Sift4G
Uncertain
0.0050
D;T;D;D
Vest4
0.97
MutPred
0.12
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
0.74
MPC
1.3
ClinPred
1.0
D
GERP RS
5.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.83

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs387907108; hg19: chr22-24718192; API