21-46162035-C-T

Variant names:

• chr21-46162035-C-T
• rs113146399
• NM_001142854.2:c.577G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001142854.2(SPATC1L):​c.577G>A​(p.Ala193Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0751 in 1,589,382 control chromosomes in the GnomAD database, including 5,339 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A193V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.061 (392 hom., cov: 32)
  • Exomes 𝑓: 0.077 (4947 hom.)
• Consequence: SPATC1L NM_001142854.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.920
• Publications: 9 publications found

Genes affected

SPATC1L (HGNC:1298): (spermatogenesis and centriole associated 1 like) Enables identical protein binding activity. Predicted to act upstream of or within several processes, including actin polymerization or depolymerization; positive regulation of cAMP-dependent protein kinase activity; and positive regulation of protein kinase A signaling. Predicted to be located in sperm connecting piece. Predicted to be active in centrosome. [provided by Alliance of Genome Resources, Apr 2022]

SPATC1L Gene-Disease associations (from GenCC):

• hearing loss disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013727844).
• BP6: Variant 21-46162035-C-T is Benign according to our data. Variant chr21-46162035-C-T is described in ClinVar as Benign. ClinVar VariationId is 403470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATC1L	NM_001142854.2	c.577G>A	p.Ala193Thr	missense_variant	Exon 4 of 5	ENST00000291672.6	NP_001136326.1
SPATC1L	NM_032261.5	c.115G>A	p.Ala39Thr	missense_variant	Exon 3 of 4		NP_115637.3
SPATC1L	XM_005261188.6	c.577G>A	p.Ala193Thr	missense_variant	Exon 4 of 5		XP_005261245.1
SPATC1L	XM_011529756.3	c.235G>A	p.Ala79Thr	missense_variant	Exon 2 of 3		XP_011528058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATC1L	ENST00000291672.6	c.577G>A	p.Ala193Thr	missense_variant	Exon 4 of 5	2	NM_001142854.2	ENSP00000291672.5
SPATC1L	ENST00000330205.10	c.115G>A	p.Ala39Thr	missense_variant	Exon 3 of 4	1		ENSP00000333869.6

Frequencies

GnomAD3 genomes AF: 0.0608 AC: 9242 AN: 152058 Hom.: 392 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0636

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0453

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0840

Gnomad OTH AF: 0.0649

GnomAD2 exomes AF: 0.0650 AC: 13135 AN: 201988 AF XY: 0.0669

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.0864

Gnomad EAS exome AF: 0.0155

Gnomad FIN exome AF: 0.0916

Gnomad NFE exome AF: 0.0884

Gnomad OTH exome AF: 0.0723

GnomAD4 exome AF: 0.0766 AC: 110119 AN: 1437208 Hom.: 4947 Cov.: 35 AF XY: 0.0762 AC XY: 54379 AN XY: 713526

African (AFR) AF: 0.0142 AC: 471 AN: 33204

American (AMR) AF: 0.0381 AC: 1604 AN: 42060

Ashkenazi Jewish (ASJ) AF: 0.0844 AC: 2166 AN: 25676

East Asian (EAS) AF: 0.0122 AC: 476 AN: 38864

South Asian (SAS) AF: 0.0545 AC: 4555 AN: 83646

European-Finnish (FIN) AF: 0.0922 AC: 4258 AN: 46172

Middle Eastern (MID) AF: 0.0625 AC: 359 AN: 5744

European-Non Finnish (NFE) AF: 0.0836 AC: 92153 AN: 1102316

Other (OTH) AF: 0.0685 AC: 4077 AN: 59526

GnomAD4 genome AF: 0.0607 AC: 9239 AN: 152174 Hom.: 392 Cov.: 32 AF XY: 0.0610 AC XY: 4542 AN XY: 74404

African (AFR) AF: 0.0169 AC: 703 AN: 41576

American (AMR) AF: 0.0635 AC: 972 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0859 AC: 298 AN: 3470

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5162

South Asian (SAS) AF: 0.0449 AC: 217 AN: 4830

European-Finnish (FIN) AF: 0.100 AC: 1060 AN: 10594

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0840 AC: 5708 AN: 67920

Other (OTH) AF: 0.0643 AC: 136 AN: 2116

Alfa AF: 0.0759 Hom.: 659

Bravo AF: 0.0558

TwinsUK AF: 0.0885 AC: 328

ALSPAC AF: 0.0815 AC: 314

ESP6500AA AF: 0.0162 AC: 71

ESP6500EA AF: 0.0851 AC: 729

ExAC AF: 0.0600 AC: 7149

Asia WGS AF: 0.0200 AC: 68 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30177775) -

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0060	.;T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.14	N
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N
PhyloP100		0.92
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.015
Sift	Benign	0.15	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.16	.;B
Vest4		0.16
MPC		0.19
ClinPred		0.0039	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

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: rs113146399; hg19: chr21-47581949; COSMIC: COSV52432453;