Genetic Variant SP8:p.Ser492Pro (chr7-20784343-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_182700.6(SP8):c.1474T>C(p.Ser492Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000529 in 1,513,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000044 ( 0 hom. )

Consequence

SP8
NM_182700.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.25261164).

BS2

High AC in GnomAdExome4 at 6 AD gene.

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.1474T>C	p.Ser492Pro	missense	Exon 2 of 2	NP_874359.2
	SP8	NM_198956.4		c.1420T>C	p.Ser474Pro	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.1474T>C	p.Ser492Pro	missense	Exon 2 of 2	ENSP00000408792.2	Q8IXZ3-4
	SP8	ENST00000361443.4	TSL:1	c.1420T>C	p.Ser474Pro	missense	Exon 3 of 3	ENSP00000354482.4	Q8IXZ3-3

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

147956

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000299

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000174

AC:

AN:

115154

AF XY:

0.0000157

show subpopulations

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:

0.0000462

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000439

AC:

AN:

1365632

Hom.:

Cov.:

AF XY:

0.00000742

AC XY:

AN XY:

673938

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29032

American (AMR)

AF:

0.00

AC:

AN:

33896

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24570

East Asian (EAS)

AF:

0.00

AC:

AN:

34046

South Asian (SAS)

AF:

0.00

AC:

AN:

77284

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33812

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4066

European-Non Finnish (NFE)

AF:

0.00000560

AC:

AN:

1071994

Other (OTH)

AF:

0.00

AC:

AN:

56932

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000135

AC:

AN:

147956

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72172

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

39728

American (AMR)

AF:

0.00

AC:

AN:

14974

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3422

East Asian (EAS)

AF:

0.00

AC:

AN:

5012

South Asian (SAS)

AF:

0.00

AC:

AN:

4508

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10298

Middle Eastern (MID)

AF:

0.00

AC:

AN:

308

European-Non Finnish (NFE)

AF:

0.0000299

AC:

AN:

66798

Other (OTH)

AF:

0.00

AC:

AN:

2004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

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

0.18

BayesDel_addAF

Benign

0.0066

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.83

M_CAP

Benign

0.029

MetaRNN

Benign

0.25

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

2.9

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.14

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.017

Polyphen

0.99

Vest4

0.44

MutPred

0.33

Loss of helix (P = 0.0138)

MVP

0.43

ClinPred

0.69

GERP RS

4.5

Varity_R

0.61

gMVP

0.69

Mutation Taster

=9/91

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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