chr2-170716727-A-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001003845.3(SP5):c.520A>G(p.Thr174Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000015 in 1,334,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SP5
NM_001003845.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.482

Publications

0 publications found

Variant links:

Genes affected

SP5 (HGNC:14529): (Sp5 transcription factor) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within bone morphogenesis; cellular response to organic cyclic compound; and post-anal tail morphogenesis. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

SP5 links:

ERICH2-DT (HGNC:55686): (ERICH2 divergent transcript)

ERICH2-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.044285506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP5	NM_001003845.3 link	c.520A>G	p.Thr174Ala	missense_variant	Exon 2 of 2	ENST00000375281.4	NP_001003845.1	Q6BEB4
SP5	XM_005246542.5 link	c.652A>G	p.Thr218Ala	missense_variant	Exon 2 of 2		XP_005246599.1
SP5	XM_047444264.1 link	c.292A>G	p.Thr98Ala	missense_variant	Exon 2 of 2		XP_047300220.1
ERICH2-DT	NR_110185.1 link	n.376+6777T>C		intron_variant	Intron 5 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP5	ENST00000375281.4 link	c.520A>G	p.Thr174Ala	missense_variant	Exon 2 of 2	1	NM_001003845.3	ENSP00000364430.3		Q6BEB4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

83900

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000150

AC:

AN:

1334252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

657882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26550

American (AMR)

AF:

0.00

AC:

AN:

27626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22878

East Asian (EAS)

AF:

0.00

AC:

AN:

30088

South Asian (SAS)

AF:

0.0000138

AC:

AN:

72722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36892

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3982

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1058152

Other (OTH)

AF:

0.0000181

AC:

AN:

55362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.520A>G (p.T174A) alteration is located in exon 2 (coding exon 2) of the SP5 gene. This alteration results from a A to G substitution at nucleotide position 520, causing the threonine (T) at amino acid position 174 to be replaced by an alanine (A). 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

Benign

0.10

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.074

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.32

M_CAP

Benign

0.045

MetaRNN

Benign

0.044

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.0

PhyloP100

0.48

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.060

REVEL

Benign

0.062

Sift

Benign

0.80

Sift4G

Benign

0.46

Polyphen

0.0

Vest4

0.090

MutPred

0.26

Loss of glycosylation at T174 (P = 6e-04);

MVP

0.048

ClinPred

0.032

GERP RS

-0.73

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.040

gMVP

0.25

Mutation Taster

=91/9

polymorphism

(source)

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

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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