chr22-24414562-G-A

Variant names:

• chr22-24414562-G-A
• rs1555874726
• NM_015330.6:c.3293G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPECC1L NM_015330.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 9.77
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-24414562-G-A is Pathogenic according to our data. Variant chr22-24414562-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 445948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015330.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1L	NM_015330.6	MANE Select	c.3293G>A	p.Arg1098Gln	missense	Exon 17 of 17	NP_056145.5
	SPECC1L	NM_001145468.4		c.3293G>A	p.Arg1098Gln	missense	Exon 16 of 16	NP_001138940.4
	SPECC1L	NM_001254732.3		c.3176G>A	p.Arg1059Gln	missense	Exon 15 of 15	NP_001241661.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1L	ENST00000314328.14	TSL:1 MANE Select	c.3293G>A	p.Arg1098Gln	missense	Exon 17 of 17	ENSP00000325785.8
	SPECC1L	ENST00000437398.5	TSL:1	c.3293G>A	p.Arg1098Gln	missense	Exon 16 of 16	ENSP00000393363.1
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.*679G>A		non_coding_transcript_exon	Exon 18 of 20	ENSP00000351480.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Aug 28, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31953237, 30472488)

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Teebi hypertelorism syndrome 1 Pathogenic:2

Apr 04, 2025

Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 06, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Teebi hypertelorism syndrome Pathogenic:1

Jun 01, 2018

Dept of Genetics, Assistance Publique-Hôpitaux de Paris (APHP) - R DEBRE University Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

SPECC1L-related syndrome Pathogenic:1

Aug 21, 2020

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Pathogenic	0.98	D
PhyloP100		9.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.84
MutPred		0.32		Gain of helix (P = 0.1736)
MVP		0.93
MPC		1.3
ClinPred		1.0	D
GERP RS		5.8
gMVP		0.79
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555874726; hg19: chr22-24810530;