21-46162035-C-A

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001142854.2(SPATC1L):​c.577G>T​(p.Ala193Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000696 in 1,437,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A193T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SPATC1L NM_001142854.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.920
• Publications: 0 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: AR, AD Classification: MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.050746858).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142854.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPATC1L	NM_001142854.2	MANE Select	c.577G>T	p.Ala193Ser	missense	Exon 4 of 5	NP_001136326.1	Q9H0A9-1
	SPATC1L	NM_032261.5		c.115G>T	p.Ala39Ser	missense	Exon 3 of 4	NP_115637.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SPATC1L	ENST00000291672.6	TSL:2 MANE Select	c.577G>T	p.Ala193Ser	missense	Exon 4 of 5	ENSP00000291672.5	Q9H0A9-1
	SPATC1L	ENST00000330205.10	TSL:1	c.115G>T	p.Ala39Ser	missense	Exon 3 of 4	ENSP00000333869.6	Q9H0A9-2
	SPATC1L	ENST00000872418.1		c.577G>T	p.Ala193Ser	missense	Exon 3 of 4	ENSP00000542477.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437326 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 713596

African (AFR) AF: 0.00 AC: 0 AN: 33204

American (AMR) AF: 0.00 AC: 0 AN: 42064

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38864

South Asian (SAS) AF: 0.00 AC: 0 AN: 83654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46212

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102378

Other (OTH) AF: 0.00 AC: 0 AN: 59530

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	16
DANN	Benign	0.93
DEOGEN2	Benign	0.0044	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.23	N
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N
PhyloP100		0.92
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.017
Sift	Benign	0.43	T
Sift4G	Benign	0.55	T
Polyphen		0.0020	B
Vest4		0.17
MutPred		0.24		Loss of helix (P = 0.028)
MVP		0.16
MPC		0.16
ClinPred		0.29	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.16
Mutation Taster		=96/4	polymorphism

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;