rs1556181412

Variant names:

• chr22-24302318-A-T
• rs1556181412
• NM_015330.6:c.87A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015330.6(SPECC1L):​c.87A>T​(p.Glu29Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPECC1L NM_015330.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: -1.96

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034600794).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPECC1L	NM_015330.6	c.87A>T	p.Glu29Asp	missense_variant	Exon 3 of 17	ENST00000314328.14	NP_056145.5
SPECC1L	NM_001145468.4	c.87A>T	p.Glu29Asp	missense_variant	Exon 2 of 16		NP_001138940.4
SPECC1L	NM_001254732.3	c.87A>T	p.Glu29Asp	missense_variant	Exon 2 of 15		NP_001241661.3
SPECC1L-ADORA2A	NR_103546.1	n.395A>T		non_coding_transcript_exon_variant	Exon 3 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPECC1L	ENST00000314328.14	c.87A>T	p.Glu29Asp	missense_variant	Exon 3 of 17	1	NM_015330.6	ENSP00000325785.8
SPECC1L-ADORA2A	ENST00000358654.2	n.87A>T		non_coding_transcript_exon_variant	Exon 3 of 20	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Apr 18, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SPECC1L-related disorder Uncertain:1

Apr 18, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The SPECC1L c.87A>T variant is predicted to result in the amino acid substitution p.Glu29Asp. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.9
DANN	Uncertain	0.98
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.79	.;T;.;.
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.035	T;T;T;T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.67	N;N;N;N
REVEL	Benign	0.073
Sift	Benign	0.083	T;T;T;T
Sift4G	Benign	0.32	T;T;T;T
Vest4		0.13
MutPred		0.058		Loss of methylation at K27 (P = 0.1025);Loss of methylation at K27 (P = 0.1025);Loss of methylation at K27 (P = 0.1025);Loss of methylation at K27 (P = 0.1025);
MVP		0.49
MPC		0.35
ClinPred		0.092	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.099

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: rs1556181412; hg19: chr22-24698286;