22-24302045-CAAAAAA-CAAAAAAA

Variant names:

• chr22-24302045-C-CA
• rs759458885
• NM_015330.6:c.-37-135dupA

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_015330.6(SPECC1L):​c.-37-135dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 302,576 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 31)
  • Exomes 𝑓: 0.14 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SPECC1L NM_015330.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0460
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.-37-135dupA		intron	N/A	NP_056145.5	Q69YQ0-1
	SPECC1L	NM_001145468.4		c.-37-135dupA		intron	N/A	NP_001138940.4	Q69YQ0-1
	SPECC1L	NM_001254732.3		c.-37-135dupA		intron	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.-37-150_-37-149insA		intron	N/A	ENSP00000325785.8	Q69YQ0-1
	SPECC1L	ENST00000437398.5	TSL:1	c.-37-150_-37-149insA		intron	N/A	ENSP00000393363.1	Q69YQ0-1
	SPECC1L-ADORA2A	ENST00000358654.2	TSL:2	n.-37-150_-37-149insA		intron	N/A	ENSP00000351480.2	F8WAN1

Frequencies

GnomAD3 genomes AF: 0.00242 AC: 311 AN: 128260 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00272

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00132

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.00122

Gnomad FIN AF: 0.00680

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00232

GnomAD4 exome AF: 0.145 AC: 43863 AN: 302576 Hom.: 0 AF XY: 0.146 AC XY: 23709 AN XY: 162130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.127 AC: 1043 AN: 8224

American (AMR) AF: 0.152 AC: 1872 AN: 12336

Ashkenazi Jewish (ASJ) AF: 0.164 AC: 1421 AN: 8666

East Asian (EAS) AF: 0.163 AC: 2862 AN: 17536

South Asian (SAS) AF: 0.139 AC: 4519 AN: 32552

European-Finnish (FIN) AF: 0.132 AC: 2160 AN: 16360

Middle Eastern (MID) AF: 0.165 AC: 203 AN: 1230

European-Non Finnish (NFE) AF: 0.145 AC: 27411 AN: 189360

Other (OTH) AF: 0.145 AC: 2372 AN: 16312

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00244 AC: 313 AN: 128300 Hom.: 0 Cov.: 31 AF XY: 0.00254 AC XY: 156 AN XY: 61418

African (AFR) AF: 0.00278 AC: 98 AN: 35304

American (AMR) AF: 0.00177 AC: 22 AN: 12414

Ashkenazi Jewish (ASJ) AF: 0.00132 AC: 4 AN: 3034

East Asian (EAS) AF: 0.00113 AC: 5 AN: 4444

South Asian (SAS) AF: 0.00123 AC: 5 AN: 4070

European-Finnish (FIN) AF: 0.00680 AC: 47 AN: 6908

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.00216 AC: 128 AN: 59340

Other (OTH) AF: 0.00230 AC: 4 AN: 1736

Alfa AF: 0.000895 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.046
Mutation Taster		=100/0	polymorphism

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: rs759458885; hg19: chr22-24698013;