7-20784505-C-G

Variant names:

• chr7-20784505-C-G
• rs538728047
• NM_182700.6:c.1312G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182700.6(SP8):​c.1312G>C​(p.Val438Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,098 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: 7.1e-7 (0 hom.)
• Consequence: SP8 NM_182700.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.67

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25342843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SP8	NM_182700.6	c.1312G>C	p.Val438Leu	missense_variant	Exon 2 of 2	ENST00000418710.3	NP_874359.2
SP8	NM_198956.4	c.1258G>C	p.Val420Leu	missense_variant	Exon 3 of 3		NP_945194.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SP8	ENST00000418710.3	c.1312G>C	p.Val438Leu	missense_variant	Exon 2 of 2	1	NM_182700.6	ENSP00000408792.2
SP8	ENST00000361443.4	c.1258G>C	p.Val420Leu	missense_variant	Exon 3 of 3	1		ENSP00000354482.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.09e-7 AC: 1 AN: 1410098 Hom.: 0 Cov.: 37 AF XY: 0.00000143 AC XY: 1 AN XY: 697090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 30, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1312G>C (p.V438L) alteration is located in exon 2 (coding exon 2) of the SP8 gene. This alteration results from a G to C substitution at nucleotide position 1312, causing the valine (V) at amino acid position 438 to be replaced by a leucine (L). 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	0.73
BayesDel_addAF	Benign	-0.089	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	.;.;T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.51	.;.;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-2.4	.;N;N
REVEL	Benign	0.18
Sift	Benign	0.043	.;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.80	.;.;P
Vest4		0.37
MutPred		0.35		.;.;Loss of MoRF binding (P = 0.1012);
MVP		0.33
ClinPred		0.91	D
GERP RS		4.3
Varity_R		0.62
gMVP		0.80

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

Other links and lift over

dbSNP: rs538728047; hg19: chr7-20824124;