rs786201030

chr22-24322169-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• 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:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a coiled_coil_region (size 55) in uniprot entity CYTSA_HUMAN there are 13 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 where missense usually causes diseases, SPECC1L
• 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	UniProt
SPECC1L	NM_015330.6	c.1189A>C	p.Thr397Pro	missense_variant	5/17	ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1	n.1497A>C		non_coding_transcript_exon_variant	5/20
SPECC1L	NM_001145468.4	c.1189A>C	p.Thr397Pro	missense_variant	4/16
SPECC1L	NM_001254732.3	c.1189A>C	p.Thr397Pro	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14	c.1189A>C	p.Thr397Pro	missense_variant	5/17	1	NM_015330.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

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

Invitae

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Vest4		0.87
MutPred		0.18		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		0.57
MPC		1.4
ClinPred		0.96	D
GERP RS		5.4
gMVP		0.72

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: rs786201030; hg19: chr22-24718137;