rs1555874726

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

Sel.	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	Q69YQ0-1
	SPECC1L	NM_001145468.4		c.3293G>A	p.Arg1098Gln	missense	Exon 16 of 16	NP_001138940.4	Q69YQ0-1
	SPECC1L	NM_001254732.3		c.3176G>A	p.Arg1059Gln	missense	Exon 15 of 15	NP_001241661.3	Q69YQ0-2

Ensembl Transcripts

Sel.	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	Q69YQ0-1
	SPECC1L	ENST00000437398.5	TSL:1	c.3293G>A	p.Arg1098Gln	missense	Exon 16 of 16	ENSP00000393363.1	Q69YQ0-1
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.*679G>A		non_coding_transcript_exon	Exon 18 of 20	ENSP00000351480.2	F8WAN1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	not provided (3)
2	-	-	Teebi hypertelorism syndrome 1 (2)
1	-	-	SPECC1L-related syndrome (1)
1	-	-	Teebi hypertelorism syndrome (1)

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;