22-24302045-CAAAAAA-CAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_015330.6(SPECC1L):​c.-37-135delA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 411,172 control chromosomes in the GnomAD database, including 174 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (173 hom., cov: 31)
  • Exomes 𝑓: 0.15 (1 hom.)
• Consequence: SPECC1L NM_015330.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 22-24302045-CA-C is Benign according to our data. Variant chr22-24302045-CA-C is described in ClinVar as Benign. ClinVar VariationId is 1291907.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0959 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0296 AC: 3801 AN: 128286 Hom.: 173 Cov.: 31

Gnomad AFR AF: 0.0984

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.000989

Gnomad EAS AF: 0.00112

Gnomad SAS AF: 0.000245

Gnomad FIN AF: 0.00650

Gnomad MID AF: 0.0346

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.0220

GnomAD4 exome AF: 0.154 AC: 43590 AN: 282848 Hom.: 1 AF XY: 0.154 AC XY: 23241 AN XY: 151394

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

African (AFR) AF: 0.208 AC: 1640 AN: 7898

American (AMR) AF: 0.166 AC: 1928 AN: 11614

Ashkenazi Jewish (ASJ) AF: 0.144 AC: 1190 AN: 8272

East Asian (EAS) AF: 0.157 AC: 2622 AN: 16690

South Asian (SAS) AF: 0.166 AC: 4725 AN: 28530

European-Finnish (FIN) AF: 0.150 AC: 2294 AN: 15304

Middle Eastern (MID) AF: 0.167 AC: 195 AN: 1166

European-Non Finnish (NFE) AF: 0.149 AC: 26566 AN: 177910

Other (OTH) AF: 0.157 AC: 2430 AN: 15464

⚠️ 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 AF: 0.0297 AC: 3815 AN: 128324 Hom.: 173 Cov.: 31 AF XY: 0.0292 AC XY: 1791 AN XY: 61428

African (AFR) AF: 0.0986 AC: 3480 AN: 35300

American (AMR) AF: 0.0111 AC: 138 AN: 12424

Ashkenazi Jewish (ASJ) AF: 0.000989 AC: 3 AN: 3034

East Asian (EAS) AF: 0.00112 AC: 5 AN: 4448

South Asian (SAS) AF: 0.000246 AC: 1 AN: 4072

European-Finnish (FIN) AF: 0.00650 AC: 45 AN: 6922

Middle Eastern (MID) AF: 0.0369 AC: 9 AN: 244

European-Non Finnish (NFE) AF: 0.00162 AC: 96 AN: 59334

Other (OTH) AF: 0.0218 AC: 38 AN: 1740

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

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;