chr21-46161521-T-A

Variant names:

• chr21-46161521-T-A
• rs146895208
• NM_001142854.2:c.881A>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001142854.2(SPATC1L):​c.881A>T​(p.Asn294Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,609,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: SPATC1L NM_001142854.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.401
• 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: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.029695868).
• BS2: High AC in GnomAd4 at 47 AD gene.

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.881A>T	p.Asn294Ile	missense	Exon 5 of 5	NP_001136326.1	Q9H0A9-1
	SPATC1L	NM_032261.5		c.419A>T	p.Asn140Ile	missense	Exon 4 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.881A>T	p.Asn294Ile	missense	Exon 5 of 5	ENSP00000291672.5	Q9H0A9-1
	SPATC1L	ENST00000330205.10	TSL:1	c.419A>T	p.Asn140Ile	missense	Exon 4 of 4	ENSP00000333869.6	Q9H0A9-2
	SPATC1L	ENST00000872418.1		c.881A>T	p.Asn294Ile	missense	Exon 4 of 4	ENSP00000542477.1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151754 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000968

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000109 AC: 26 AN: 239140 AF XY: 0.0000612

Gnomad AFR exome AF: 0.00127

Gnomad AMR exome AF: 0.0000884

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000104 AC: 151 AN: 1457974 Hom.: 0 Cov.: 32 AF XY: 0.0000910 AC XY: 66 AN XY: 725136

African (AFR) AF: 0.000987 AC: 33 AN: 33448

American (AMR) AF: 0.000135 AC: 6 AN: 44488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39634

South Asian (SAS) AF: 0.00 AC: 0 AN: 85988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000945 AC: 105 AN: 1110810

Other (OTH) AF: 0.000116 AC: 7 AN: 60182

GnomAD4 genome AF: 0.000309 AC: 47 AN: 151872 Hom.: 0 Cov.: 31 AF XY: 0.000256 AC XY: 19 AN XY: 74236

African (AFR) AF: 0.000989 AC: 41 AN: 41444

American (AMR) AF: 0.000327 AC: 5 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2100

Alfa AF: 0.0000848 Hom.: 0

Bravo AF: 0.000374

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000997 AC: 12

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.046	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.54	D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.14	N
PhyloP100		0.40
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.023
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.013	D
Polyphen		0.047	B
Vest4		0.32
MVP		0.32
MPC		0.50
ClinPred		0.033	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.59
Mutation Taster		=90/10	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: rs146895208; hg19: chr21-47581435;