21-46161921-C-T

Position:

• chr21-46161921-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.691G>A​(p.Glu231Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0756 in 1,605,954 control chromosomes in the GnomAD database, including 5,497 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.061 (393 hom., cov: 33)
  • Exomes 𝑓: 0.077 (5104 hom.)
• Consequence: SPATC1L NM_001142854.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.15

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=0.0014095306).
• BP6: Variant 21-46161921-C-T is Benign according to our data. Variant chr21-46161921-C-T is described in ClinVar as [Benign]. Clinvar id is 403469.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0828 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SPATC1L	NM_001142854.2	c.691G>A	p.Glu231Lys	missense_variant	4/5	ENST00000291672.6	NP_001136326.1
SPATC1L	NM_032261.5	c.229G>A	p.Glu77Lys	missense_variant	3/4		NP_115637.3
SPATC1L	XM_005261188.6	c.691G>A	p.Glu231Lys	missense_variant	4/5		XP_005261245.1
SPATC1L	XM_011529756.3	c.349G>A	p.Glu117Lys	missense_variant	2/3		XP_011528058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SPATC1L	ENST00000291672.6	c.691G>A	p.Glu231Lys	missense_variant	4/5	2	NM_001142854.2	ENSP00000291672.5
SPATC1L	ENST00000330205.10	c.229G>A	p.Glu77Lys	missense_variant	3/4	1		ENSP00000333869.6

Frequencies

GnomAD3 genomes AF: 0.0610 AC: 9280 AN: 152028 Hom.: 393 Cov.: 33

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.0859

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.0454

Gnomad FIN AF: 0.0995

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0846

Gnomad OTH AF: 0.0651

GnomAD3 exomes AF: 0.0648 AC: 15271 AN: 235782 Hom.: 633 AF XY: 0.0668 AC XY: 8654 AN XY: 129576

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0866

Gnomad EAS exome AF: 0.0151

Gnomad SAS exome AF: 0.0507

Gnomad FIN exome AF: 0.0881

Gnomad NFE exome AF: 0.0874

Gnomad OTH exome AF: 0.0751

GnomAD4 exome AF: 0.0772 AC: 112172 AN: 1453808 Hom.: 5104 Cov.: 35 AF XY: 0.0767 AC XY: 55522 AN XY: 723546

Gnomad4 AFR exome AF: 0.0143

Gnomad4 AMR exome AF: 0.0379

Gnomad4 ASJ exome AF: 0.0845

Gnomad4 EAS exome AF: 0.0123

Gnomad4 SAS exome AF: 0.0542

Gnomad4 FIN exome AF: 0.0908

Gnomad4 NFE exome AF: 0.0845

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.0610 AC: 9277 AN: 152146 Hom.: 393 Cov.: 33 AF XY: 0.0611 AC XY: 4548 AN XY: 74396

Gnomad4 AFR AF: 0.0169

Gnomad4 AMR AF: 0.0638

Gnomad4 ASJ AF: 0.0859

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.0450

Gnomad4 FIN AF: 0.0995

Gnomad4 NFE AF: 0.0846

Gnomad4 OTH AF: 0.0644

Alfa AF: 0.0784 Hom.: 247

Bravo AF: 0.0562

TwinsUK AF: 0.0887 AC: 329

ALSPAC AF: 0.0817 AC: 315

ESP6500AA AF: 0.0160 AC: 70

ESP6500EA AF: 0.0869 AC: 746

ExAC AF: 0.0658 AC: 7909

Asia WGS AF: 0.0200 AC: 69 AN: 3478

EpiCase AF: 0.0856

EpiControl AF: 0.0876

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 11, 2019	This variant is associated with the following publications: (PMID: 30177775, 28339009) -

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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.0028	.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.062	N
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	.;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.77	N;N
REVEL	Benign	0.023
Sift	Benign	1.0	T;T
Sift4G	Benign	0.89	T;T
Polyphen		0.0	.;B
Vest4		0.14
MPC		0.19
ClinPred		0.018	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.033
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

Other links and lift over

dbSNP: rs113710653; hg19: chr21-47581835; COSMIC: COSV52434259;