Genetic Variant NM_001100423.2:c.175T>C (chr2-200416405-T-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001100423.2(SPATS2L):c.175T>C(p.Trp59Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000668 in 1,347,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000067 ( 0 hom. )

Consequence

SPATS2L
NM_001100423.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.49

Publications

0 publications found

Variant links:

Genes affected

SPATS2L (HGNC:24574): (spermatogenesis associated serine rich 2 like) Enables RNA binding activity. Located in cytosol; nucleolus; and nucleoplasm. Part of protein-containing complex. [provided by Alliance of Genome Resources, Apr 2022]

SPATS2L links:

ENSG00000287299 (HGNC:):

ENSG00000287299 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.901

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SPATS2L	NM_001100423.2 link	c.175T>C	p.Trp59Arg	missense_variant	Exon 5 of 13	ENST00000409140.8	NP_001093893.1	Q9NUQ6-1A0A024R3V0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SPATS2L	ENST00000409140.8 link	c.175T>C	p.Trp59Arg	missense_variant	Exon 5 of 13	2	NM_001100423.2	ENSP00000386730.3		Q9NUQ6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000668

AC:

AN:

1347098

Hom.:

Cov.:

AF XY:

0.00000599

AC XY:

AN XY:

668196

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000334

AC:

AN:

29922

American (AMR)

AF:

0.00

AC:

AN:

33394

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24154

East Asian (EAS)

AF:

0.0000279

AC:

AN:

35892

South Asian (SAS)

AF:

0.00

AC:

AN:

68544

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5416

European-Non Finnish (NFE)

AF:

0.00000576

AC:

AN:

1042484

Other (OTH)

AF:

0.0000178

AC:

AN:

56032

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000002), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.392

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.175T>C (p.W59R) alteration is located in exon 5 (coding exon 3) of the SPATS2L gene. This alteration results from a T to C substitution at nucleotide position 175, causing the tryptophan (W) at amino acid position 59 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T;T;T;T;T;.;T;T;T;T;T;.;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;.;.;.;D;.;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Benign

0.047

MetaRNN

Pathogenic

0.90

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.7

.;M;M;M;.;M;M;.;.;.;M;.;.;.;.;.;.

PhyloP100

6.5

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-13

D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D

REVEL

Pathogenic

0.67

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D

Polyphen

1.0, 1.0

.;D;D;D;.;D;D;.;.;.;D;.;.;.;.;.;.

Vest4

0.97, 0.94, 0.98, 0.98

MutPred

0.75

Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);.;.;Gain of disorder (P = 0.0093);Gain of disorder (P = 0.0093);.;

MVP

0.59

MPC

1.3

ClinPred

1.0

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.86

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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NM_001100423.2:c.175T>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over