rs3747113

Positions:

• chr22-24321550-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_015330.6(SPECC1L):​c.570G>A​(p.Thr190=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,613,942 control chromosomes in the GnomAD database, including 53,073 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.22 (4154 hom., cov: 33)
  • Exomes 𝑓: 0.26 (48919 hom.)
• Consequence: SPECC1L NM_015330.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.42

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 22-24321550-G-A is Benign according to our data. Variant chr22-24321550-G-A is described in ClinVar as [Benign]. Clinvar id is 1282641.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-24321550-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-3.42 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPECC1L	NM_015330.6	c.570G>A	p.Thr190=	synonymous_variant	5/17	ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1	n.878G>A		non_coding_transcript_exon_variant	5/20
SPECC1L	NM_001145468.4	c.570G>A	p.Thr190=	synonymous_variant	4/16
SPECC1L	NM_001254732.3	c.570G>A	p.Thr190=	synonymous_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14	c.570G>A	p.Thr190=	synonymous_variant	5/17	1	NM_015330.6	P1

Frequencies

GnomAD3 genomes AF: 0.225 AC: 34189 AN: 152028 Hom.: 4150 Cov.: 33

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.231

Gnomad SAS AF: 0.173

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.233

GnomAD3 exomes AF: 0.245 AC: 61636 AN: 251396 Hom.: 8016 AF XY: 0.242 AC XY: 32897 AN XY: 135882

Gnomad AFR exome AF: 0.136

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.234

Gnomad EAS exome AF: 0.226

Gnomad SAS exome AF: 0.180

Gnomad FIN exome AF: 0.243

Gnomad NFE exome AF: 0.258

Gnomad OTH exome AF: 0.257

GnomAD4 exome AF: 0.256 AC: 374357 AN: 1461796 Hom.: 48919 Cov.: 38 AF XY: 0.253 AC XY: 184208 AN XY: 727210

Gnomad4 AFR exome AF: 0.136

Gnomad4 AMR exome AF: 0.327

Gnomad4 ASJ exome AF: 0.238

Gnomad4 EAS exome AF: 0.268

Gnomad4 SAS exome AF: 0.181

Gnomad4 FIN exome AF: 0.243

Gnomad4 NFE exome AF: 0.264

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.225 AC: 34219 AN: 152146 Hom.: 4154 Cov.: 33 AF XY: 0.226 AC XY: 16777 AN XY: 74382

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.291

Gnomad4 ASJ AF: 0.233

Gnomad4 EAS AF: 0.232

Gnomad4 SAS AF: 0.172

Gnomad4 FIN AF: 0.252

Gnomad4 NFE AF: 0.263

Gnomad4 OTH AF: 0.237

Alfa AF: 0.254 Hom.: 6945

Bravo AF: 0.226

Asia WGS AF: 0.222 AC: 773 AN: 3478

EpiCase AF: 0.260

EpiControl AF: 0.260

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2020	- -

Teebi hypertelorism syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Autosomal dominant Opitz G/BBB syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Oculomaxillofacial dysostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.38
DANN	Benign	0.64

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: rs3747113; hg19: chr22-24717518; COSMIC: COSV58657272;