Genetic Variant SP8:p.Ala484Thr (chr7-20784367-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

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

The NM_182700.6(SP8):c.1450G>A(p.Ala484Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,372,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

SP8
NM_182700.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.200

Publications

0 publications found

Variant links:

Genes affected

SP8 (HGNC:19196): (Sp8 transcription factor) The protein encoded by this gene is an SP family transcription factor that in mouse has been shown to be essential for proper limb development. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

SP8 links:

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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=0.0417279).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182700.6. 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
	SP8	NM_182700.6	MANE Select	c.1450G>A	p.Ala484Thr	missense	Exon 2 of 2	NP_874359.2
	SP8	NM_198956.4		c.1396G>A	p.Ala466Thr	missense	Exon 3 of 3	NP_945194.1	Q8IXZ3-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SP8	ENST00000418710.3	TSL:1 MANE Select	c.1450G>A	p.Ala484Thr	missense	Exon 2 of 2	ENSP00000408792.2	Q8IXZ3-4
	SP8	ENST00000361443.4	TSL:1	c.1396G>A	p.Ala466Thr	missense	Exon 3 of 3	ENSP00000354482.4	Q8IXZ3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1372568

Hom.:

Cov.:

AF XY:

0.00000295

AC XY:

AN XY:

677182

show subpopulations

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

African (AFR)

AF:

0.0000335

AC:

AN:

29810

American (AMR)

AF:

0.00

AC:

AN:

35018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24842

East Asian (EAS)

AF:

0.00

AC:

AN:

34806

South Asian (SAS)

AF:

0.00

AC:

AN:

78074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4052

European-Non Finnish (NFE)

AF:

9.30e-7

AC:

AN:

1074854

Other (OTH)

AF:

0.00

AC:

AN:

57300

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

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.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.54

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.67

M_CAP

Benign

0.011

MetaRNN

Benign

0.042

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.20

PhyloP100

-0.20

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.50

REVEL

Benign

0.065

Sift

Benign

0.48

Sift4G

Benign

0.58

Polyphen

0.14

Vest4

0.12

MutPred

0.33

Gain of glycosylation at A466 (P = 0.0118)

MVP

0.11

ClinPred

0.21

GERP RS

3.7

Varity_R

0.074

gMVP

0.50

Mutation Taster

=82/18

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over