21-46161509-C-T

Variant names:

• chr21-46161509-C-T
• rs14378
• NM_001142854.2:c.893G>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.893G>A​(p.Ser298Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0926 in 1,607,716 control chromosomes in the GnomAD database, including 7,828 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. S298G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.10 (970 hom., cov: 31)
  • Exomes 𝑓: 0.091 (6858 hom.)
• Consequence: SPATC1L NM_001142854.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.10
• Publications: 10 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=0.0012110174).
• BP6: Variant 21-46161509-C-T is Benign according to our data. Variant chr21-46161509-C-T is described in ClinVar as Benign. ClinVar VariationId is 403468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATC1L	NM_001142854.2	c.893G>A	p.Ser298Asn	missense_variant	Exon 5 of 5	ENST00000291672.6	NP_001136326.1
SPATC1L	NM_032261.5	c.431G>A	p.Ser144Asn	missense_variant	Exon 4 of 4		NP_115637.3
SPATC1L	XM_005261188.6	c.893G>A	p.Ser298Asn	missense_variant	Exon 5 of 5		XP_005261245.1
SPATC1L	XM_011529756.3	c.551G>A	p.Ser184Asn	missense_variant	Exon 3 of 3		XP_011528058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATC1L	ENST00000291672.6	c.893G>A	p.Ser298Asn	missense_variant	Exon 5 of 5	2	NM_001142854.2	ENSP00000291672.5
SPATC1L	ENST00000330205.10	c.431G>A	p.Ser144Asn	missense_variant	Exon 4 of 4	1		ENSP00000333869.6

Frequencies

GnomAD3 genomes AF: 0.105 AC: 15879 AN: 151942 Hom.: 962 Cov.: 31

Gnomad AFR AF: 0.141

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.0877

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.0176

Gnomad SAS AF: 0.120

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.111

GnomAD2 exomes AF: 0.0891 AC: 21199 AN: 238008 AF XY: 0.0913

Gnomad AFR exome AF: 0.146

Gnomad AMR exome AF: 0.0497

Gnomad ASJ exome AF: 0.0991

Gnomad EAS exome AF: 0.0191

Gnomad FIN exome AF: 0.0963

Gnomad NFE exome AF: 0.0952

Gnomad OTH exome AF: 0.0878

GnomAD4 exome AF: 0.0914 AC: 132979 AN: 1455656 Hom.: 6858 Cov.: 33 AF XY: 0.0920 AC XY: 66568 AN XY: 723542

African (AFR) AF: 0.142 AC: 4739 AN: 33376

American (AMR) AF: 0.0527 AC: 2337 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.0966 AC: 2512 AN: 26006

East Asian (EAS) AF: 0.0146 AC: 578 AN: 39534

South Asian (SAS) AF: 0.117 AC: 10095 AN: 85922

European-Finnish (FIN) AF: 0.0965 AC: 4970 AN: 51518

Middle Eastern (MID) AF: 0.0824 AC: 474 AN: 5750

European-Non Finnish (NFE) AF: 0.0918 AC: 101794 AN: 1109100

Other (OTH) AF: 0.0912 AC: 5480 AN: 60066

GnomAD4 genome AF: 0.105 AC: 15928 AN: 152060 Hom.: 970 Cov.: 31 AF XY: 0.105 AC XY: 7807 AN XY: 74336

African (AFR) AF: 0.142 AC: 5894 AN: 41494

American (AMR) AF: 0.0875 AC: 1339 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0988 AC: 343 AN: 3472

East Asian (EAS) AF: 0.0175 AC: 90 AN: 5156

South Asian (SAS) AF: 0.119 AC: 575 AN: 4832

European-Finnish (FIN) AF: 0.101 AC: 1066 AN: 10580

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0916 AC: 6224 AN: 67922

Other (OTH) AF: 0.116 AC: 244 AN: 2108

Alfa AF: 0.0961 Hom.: 1106

Bravo AF: 0.103

TwinsUK AF: 0.0963 AC: 357

ALSPAC AF: 0.0913 AC: 352

ESP6500AA AF: 0.136 AC: 597

ESP6500EA AF: 0.0943 AC: 809

ExAC AF: 0.0918 AC: 11030

Asia WGS AF: 0.104 AC: 359 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	0.17
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	21
DANN	Benign	0.93
DEOGEN2	Benign	0.0054	.;T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.0012	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.0	.;N
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.11
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.070
MPC		0.16
ClinPred		0.0090	T
GERP RS		3.3
Varity_R		0.059
gMVP		0.29
Mutation Taster		=97/3	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: rs14378; hg19: chr21-47581423; COSMIC: COSV52432428;