rs387907108

Variant names:

• chr22-24322224-A-C
• rs387907108
• NM_015330.6:c.1244A>C

Your query was ambiguous. Multiple possible variants found:

• chr22-24322224-A-C
• chr22-24322224-A-G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP5

The NM_015330.6(SPECC1L):​c.1244A>C​(p.Gln415Pro) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q415R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPECC1L NM_015330.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.12
• Publications: 7 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 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_015330.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-24322224-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2704383.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP5: Variant 22-24322224-A-C is Pathogenic according to our data. Variant chr22-24322224-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 31101.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPECC1L	NM_015330.6	c.1244A>C	p.Gln415Pro	missense_variant	Exon 5 of 17	ENST00000314328.14	NP_056145.5
SPECC1L	NM_001145468.4	c.1244A>C	p.Gln415Pro	missense_variant	Exon 4 of 16		NP_001138940.4
SPECC1L	NM_001254732.3	c.1244A>C	p.Gln415Pro	missense_variant	Exon 4 of 15		NP_001241661.3
SPECC1L-ADORA2A	NR_103546.1	n.1552A>C		non_coding_transcript_exon_variant	Exon 5 of 20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPECC1L	ENST00000314328.14	c.1244A>C	p.Gln415Pro	missense_variant	Exon 5 of 17	1	NM_015330.6	ENSP00000325785.8
SPECC1L-ADORA2A	ENST00000358654.2	n.1244A>C		non_coding_transcript_exon_variant	Exon 5 of 20	2		ENSP00000351480.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Oculomaxillofacial dysostosis Pathogenic:1

Jul 15, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	.;D;.;.
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Benign	-1.1	T
PhyloP100		9.1
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0050	D;T;D;D
Vest4		0.97
MutPred		0.12		Gain of glycosylation at Q415 (P = 0.0306);Gain of glycosylation at Q415 (P = 0.0306);Gain of glycosylation at Q415 (P = 0.0306);Gain of glycosylation at Q415 (P = 0.0306);
MVP		0.74
MPC		1.3
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.83
Mutation Taster		=7/93	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: rs387907108; hg19: chr22-24718192;