rs1556226291

Positions:

• chr22-24322272-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP5_Moderate

The NM_015330.6(SPECC1L):​c.1292T>C​(p.Leu431Pro) 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: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a coiled_coil_region (size 55) in uniprot entity CYTSA_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_015330.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SPECC1L
• PP5: Variant 22-24322272-T-C is Pathogenic according to our data. Variant chr22-24322272-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559898.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPECC1L	NM_015330.6	c.1292T>C	p.Leu431Pro	missense_variant	5/17	ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1	n.1600T>C		non_coding_transcript_exon_variant	5/20
SPECC1L	NM_001145468.4	c.1292T>C	p.Leu431Pro	missense_variant	4/16
SPECC1L	NM_001254732.3	c.1292T>C	p.Leu431Pro	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14	c.1292T>C	p.Leu431Pro	missense_variant	5/17	1	NM_015330.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant Opitz G/BBB syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Aug 03, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Vest4		0.95
MutPred		0.35		Gain of glycosylation at L431 (P = 0.0334);Gain of glycosylation at L431 (P = 0.0334);Gain of glycosylation at L431 (P = 0.0334);Gain of glycosylation at L431 (P = 0.0334);
MVP		0.71
MPC		1.6
ClinPred		1.0	D
GERP RS		5.0
gMVP		0.96

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: rs1556226291; hg19: chr22-24718240;