Genetic Variant NM_015330.6:c.3293G>A (chr22-24414562-G-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 9.77

Publications

1 publications found

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 links:

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]

SPECC1L-ADORA2A links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPECC1L	NM_015330.6 link	c.3293G>A	p.Arg1098Gln	missense_variant	Exon 17 of 17	ENST00000314328.14	NP_056145.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SPECC1L	ENST00000314328.14 link	c.3293G>A	p.Arg1098Gln	missense_variant	Exon 17 of 17	1	NM_015330.6	ENSP00000325785.8
SPECC1L-ADORA2A	ENST00000358654.2 link	n.*679G>A		non_coding_transcript_exon_variant	Exon 18 of 20	2		ENSP00000351480.2
SPECC1L-ADORA2A	ENST00000358654.2 link	n.*679G>A		3_prime_UTR_variant	Exon 18 of 20	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

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) -

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

- -

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 06, 2022

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.49

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.90

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

1.0

M_CAP

Pathogenic

0.47

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Pathogenic

0.98

PhyloP100

9.8

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.6

D;D;D

REVEL

Pathogenic

0.73

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.84

MutPred

0.32

Gain of helix (P = 0.1736);Gain of helix (P = 0.1736);.;

MVP

0.93

MPC

1.3

ClinPred

1.0

GERP RS

5.8

gMVP

0.79

Mutation Taster

=2/98

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over