rs786201030

Variant names:

• chr22-24322169-A-C
• rs786201030
• NM_015330.6:c.1189A>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_015330.6(SPECC1L):​c.1189A>C​(p.Thr397Pro) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SPECC1L NM_015330.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.12
• Publications: 6 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]

ENSG00000299949 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_015330.6
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-24322169-A-C is Pathogenic according to our data. Variant chr22-24322169-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 183671.Status of the report is criteria_provided_single_submitter, 1 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.1189A>C	p.Thr397Pro	missense	Exon 5 of 17	NP_056145.5
	SPECC1L	NM_001145468.4		c.1189A>C	p.Thr397Pro	missense	Exon 4 of 16	NP_001138940.4
	SPECC1L	NM_001254732.3		c.1189A>C	p.Thr397Pro	missense	Exon 4 of 15	NP_001241661.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPECC1L	ENST00000314328.14	TSL:1 MANE Select	c.1189A>C	p.Thr397Pro	missense	Exon 5 of 17	ENSP00000325785.8
	SPECC1L	ENST00000437398.5	TSL:1	c.1189A>C	p.Thr397Pro	missense	Exon 4 of 16	ENSP00000393363.1
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.1189A>C		non_coding_transcript_exon	Exon 5 of 20	ENSP00000351480.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Teebi hypertelorism syndrome (1)
1	-	-	Teebi hypertelorism syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-1.1	T
PhyloP100		9.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Vest4		0.87
MutPred		0.18		Loss of catalytic residue at T397 (P = 0.075)
MVP		0.57
MPC		1.4
ClinPred		0.96	D
GERP RS		5.4
gMVP		0.72
Mutation Taster		=3/97	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: rs786201030; hg19: chr22-24718137;