22-24302389-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015330.6(SPECC1L):c.153+5T>G variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,030 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (14 hom.)
• Consequence: SPECC1L NM_015330.6 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.0001867
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.158

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 22-24302389-T-G is Benign according to our data. Variant chr22-24302389-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 731574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00251 (382/152338) while in subpopulation NFE AF= 0.00437 (297/68032). AF 95% confidence interval is 0.00396. There are 1 homozygotes in gnomad4. There are 178 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 382 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPECC1L	NM_015330.6	c.153+5T>G		splice_donor_5th_base_variant, intron_variant		ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1	n.461+5T>G		splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant
SPECC1L	NM_001145468.4	c.153+5T>G		splice_donor_5th_base_variant, intron_variant
SPECC1L	NM_001254732.3	c.153+5T>G		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14	c.153+5T>G		splice_donor_5th_base_variant, intron_variant		1	NM_015330.6	P1

Frequencies

GnomAD3 genomes AF: 0.00251 AC: 382 AN: 152220 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00437

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00237 AC: 591 AN: 249650 Hom.: 2 AF XY: 0.00233 AC XY: 315 AN XY: 135216

Gnomad AFR exome AF: 0.000809

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000655

Gnomad FIN exome AF: 0.00425

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00374 AC: 5470 AN: 1461692 Hom.: 14 Cov.: 31 AF XY: 0.00364 AC XY: 2645 AN XY: 727152

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000591

Gnomad4 FIN exome AF: 0.00366

Gnomad4 NFE exome AF: 0.00453

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.00251 AC: 382 AN: 152338 Hom.: 1 Cov.: 32 AF XY: 0.00239 AC XY: 178 AN XY: 74490

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00386

Gnomad4 NFE AF: 0.00437

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00341 Hom.: 2

Bravo AF: 0.00208

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00393

EpiControl AF: 0.00249

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Nov 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	SPECC1L: BP4, BS2 -

Oculomaxillofacial dysostosis;CN306405:Teebi hypertelorism syndrome 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 30, 2021

- -

SPECC1L-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 04, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.0
Dann	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.028
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: rs143374533; hg19: chr22-24698357;