Genetic Variant SP8:p.Arg342His (chr7-20784792-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_182700.6(SP8):c.1025G>A(p.Arg342His) variant causes a missense change. The variant allele was found at a frequency of 0.000000722 in 1,384,476 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: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

SP8
NM_182700.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.65

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 made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27386796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP8	NM_182700.6 link	c.1025G>A	p.Arg342His	missense_variant	Exon 2 of 2	ENST00000418710.3	NP_874359.2	Q8IXZ3-4A8K350
SP8	NM_198956.4 link	c.971G>A	p.Arg324His	missense_variant	Exon 3 of 3		NP_945194.1	Q8IXZ3-3A8K350

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP8	ENST00000418710.3 link	c.1025G>A	p.Arg342His	missense_variant	Exon 2 of 2	1	NM_182700.6	ENSP00000408792.2		Q8IXZ3-4
SP8	ENST00000361443.4 link	c.971G>A	p.Arg324His	missense_variant	Exon 3 of 3	1		ENSP00000354482.4		Q8IXZ3-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000758

AC:

AN:

131878

Hom.:

AF XY:

0.0000137

AC XY:

AN XY:

72850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000994

Gnomad SAS 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:

7.22e-7

AC:

AN:

1384476

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684014

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000282

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1025G>A (p.R342H) alteration is located in exon 2 (coding exon 2) of the SP8 gene. This alteration results from a G to A substitution at nucleotide position 1025, causing the arginine (R) at amino acid position 342 to be replaced by a histidine (H). 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

0.68

BayesDel_addAF

Benign

-0.093

BayesDel_noAF

Benign

-0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;.;D

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.83

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.9

.;.;M

PrimateAI

Pathogenic

0.95

PROVEAN

Pathogenic

-4.5

.;D;D

REVEL

Benign

0.16

Sift

Uncertain

0.0020

.;D;D

Sift4G

Uncertain

0.0070

D;D;D

Polyphen

0.96

.;.;P

Vest4

0.29

MutPred

0.45

.;.;Loss of MoRF binding (P = 0.0142);

MVP

0.27

ClinPred

0.98

GERP RS

3.3

Varity_R

0.67

gMVP

0.73

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over