21-46161509-C-T

Position:

• chr21-46161509-C-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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:2
• Conservation: PhyloP100: 1.10

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
SPATC1L	NM_001142854.2	c.893G>A	p.Ser298Asn	missense_variant	5/5	ENST00000291672.6
SPATC1L	NM_032261.5	c.431G>A	p.Ser144Asn	missense_variant	4/4
SPATC1L	XM_005261188.6	c.893G>A	p.Ser298Asn	missense_variant	5/5
SPATC1L	XM_011529756.3	c.551G>A	p.Ser184Asn	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPATC1L	ENST00000291672.6	c.893G>A	p.Ser298Asn	missense_variant	5/5	2	NM_001142854.2	P1
SPATC1L	ENST00000330205.10	c.431G>A	p.Ser144Asn	missense_variant	4/4	1

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

GnomAD3 exomes AF: 0.0891 AC: 21199 AN: 238008 Hom.: 1112 AF XY: 0.0913 AC XY: 11869 AN XY: 130014

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 SAS exome AF: 0.117

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

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.0527

Gnomad4 ASJ exome AF: 0.0966

Gnomad4 EAS exome AF: 0.0146

Gnomad4 SAS exome AF: 0.117

Gnomad4 FIN exome AF: 0.0965

Gnomad4 NFE exome AF: 0.0918

Gnomad4 OTH exome AF: 0.0912

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

Gnomad4 AFR AF: 0.142

Gnomad4 AMR AF: 0.0875

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.0175

Gnomad4 SAS AF: 0.119

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0916

Gnomad4 OTH AF: 0.116

Alfa AF: 0.0917 Hom.: 648

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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 -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 19, 2019

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

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
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
MutationTaster	Benign	0.89	P;P
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

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

Other links and lift over

dbSNP: rs14378; hg19: chr21-47581423; COSMIC: COSV52432428;