22-24321542-C-T

Position:

chr22-24321542-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_015330.6(SPECC1L):c.562C>T(p.Leu188Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00654 in 1,614,182 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0074 ( 10 hom., cov: 33)

Exomes 𝑓: 0.0064 ( 61 hom. )

Consequence

SPECC1L
NM_015330.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.34

Variant links:

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 links:

SPECC1L-ADORA2A (HGNC:):

SPECC1L-ADORA2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SPECC1L. . Gene score misZ 1.5985 (greater than the threshold 3.09). Trascript score misZ 3.1934 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant Opitz G/BBB syndrome, hypertelorism, Teebi type, commissural facial cleft, Tessier number 4 facial cleft.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059348345).

BP6

Variant 22-24321542-C-T is Benign according to our data. Variant chr22-24321542-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445410.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-24321542-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00744 (1134/152322) while in subpopulation AMR AF= 0.00849 (130/15310). AF 95% confidence interval is 0.00751. There are 10 homozygotes in gnomad4. There are 623 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
SPECC1L	NM_015330.6 linkuse as main transcript	c.562C>T	p.Leu188Phe	missense_variant	5/17	ENST00000314328.14
SPECC1L-ADORA2A	NR_103546.1 linkuse as main transcript	n.870C>T		non_coding_transcript_exon_variant	5/20
SPECC1L	NM_001145468.4 linkuse as main transcript	c.562C>T	p.Leu188Phe	missense_variant	4/16
SPECC1L	NM_001254732.3 linkuse as main transcript	c.562C>T	p.Leu188Phe	missense_variant	4/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPECC1L	ENST00000314328.14 linkuse as main transcript	c.562C>T	p.Leu188Phe	missense_variant	5/17	1	NM_015330.6	P1	Q69YQ0-1

Frequencies

GnomAD3 genomes

AF:

0.00745

AC:

1134

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.0318

Gnomad AMR

AF:

0.00850

Gnomad ASJ

AF:

0.00836

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0308

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00807

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00767

AC:

1930

AN:

251468

Hom.:

AF XY:

0.00781

AC XY:

1061

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.00408

Gnomad ASJ exome

AF:

0.0106

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00134

Gnomad FIN exome

AF:

0.0294

Gnomad NFE exome

AF:

0.00819

Gnomad OTH exome

AF:

0.00961

GnomAD4 exome

AF:

0.00644

AC:

9415

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00642

AC XY:

4667

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.000836

Gnomad4 AMR exome

AF:

0.00443

Gnomad4 ASJ exome

AF:

0.00884

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00143

Gnomad4 FIN exome

AF:

0.0265

Gnomad4 NFE exome

AF:

0.00626

Gnomad4 OTH exome

AF:

0.00619

GnomAD4 genome

AF:

0.00744

AC:

1134

AN:

152322

Hom.:

Cov.:

AF XY:

0.00836

AC XY:

623

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00849

Gnomad4 ASJ

AF:

0.00836

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.0308

Gnomad4 NFE

AF:

0.00807

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.0145

Hom.:

747

Bravo

AF:

0.00587

TwinsUK

AF:

0.00512

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00802

AC:

ExAC

AF:

0.00723

AC:

878

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00889

EpiControl

AF:

0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SPECC1L: BS1, BS2 -

Oculomaxillofacial dysostosis;CN306405:Teebi hypertelorism syndrome 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.76

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

DANN

Uncertain

1.0

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Uncertain

0.92

LIST_S2

Pathogenic

0.98

.;D;.;.;D

MetaRNN

Benign

0.0059

T;T;T;T;T

MetaSVM

Uncertain

0.038

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-2.0

N;N;N;N;D

REVEL

Benign

0.25

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Vest4

0.75

MVP

0.72

MPC

1.3

ClinPred

0.017

GERP RS

5.6

gMVP

0.43

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over