22-24322169-ACT-CCG

Variant names:

• chr22-24322169-ACT-CCG
• NM_015330.6:c.1189_1191delACTinsCCG
• SPECC1L p.Thr397Pro

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PS1 PM1 PP3

The NM_015330.6(SPECC1L):​c.1189_1191delACTinsCCG​(p.Thr397Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SPECC1L NM_015330.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.12
• Publications: 0 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.

• PS1: Transcript NM_015330.6 (SPECC1L) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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.1189_1191delACTinsCCG	p.Thr397Pro	missense	N/A	NP_056145.5	Q69YQ0-1
	SPECC1L	NM_001145468.4		c.1189_1191delACTinsCCG	p.Thr397Pro	missense	N/A	NP_001138940.4	Q69YQ0-1
	SPECC1L	NM_001254732.3		c.1189_1191delACTinsCCG	p.Thr397Pro	missense	N/A	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.1189_1191delACTinsCCG	p.Thr397Pro	missense	N/A	ENSP00000325785.8	Q69YQ0-1
	SPECC1L	ENST00000437398.5	TSL:1	c.1189_1191delACTinsCCG	p.Thr397Pro	missense	N/A	ENSP00000393363.1	Q69YQ0-1
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.1189_1191delACTinsCCG		non_coding_transcript_exon	Exon 5 of 20	ENSP00000351480.2	F8WAN1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr22-24718137;