chr7-20784521-C-A

Variant names:

• chr7-20784521-C-A
• rs369276986
• NM_182700.6:c.1296G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_182700.6(SP8):​c.1296G>T​(p.Lys432Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000704 in 1,419,478 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. K432K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SP8 NM_182700.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.10
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1296G>T	p.Lys432Asn	missense	Exon 2 of 2	NP_874359.2
	SP8	NM_198956.4		c.1242G>T	p.Lys414Asn	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.1296G>T	p.Lys432Asn	missense	Exon 2 of 2	ENSP00000408792.2	Q8IXZ3-4
	SP8	ENST00000361443.4	TSL:1	c.1242G>T	p.Lys414Asn	missense	Exon 3 of 3	ENSP00000354482.4	Q8IXZ3-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.04e-7 AC: 1 AN: 1419478 Hom.: 0 Cov.: 38 AF XY: 0.00000142 AC XY: 1 AN XY: 702570

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

African (AFR) AF: 0.00 AC: 0 AN: 32424

American (AMR) AF: 0.00 AC: 0 AN: 38322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 37228

South Asian (SAS) AF: 0.00 AC: 0 AN: 81456

European-Finnish (FIN) AF: 0.0000207 AC: 1 AN: 48350

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5590

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1091800

Other (OTH) AF: 0.00 AC: 0 AN: 58882

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	0.077
Eigen_PC	Benign	-0.00046
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.83	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.1
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.030	D
Polyphen		0.99	D
Vest4		0.63
MutPred		0.36		Loss of methylation at K414 (P = 0.0011)
MVP		0.58
ClinPred		1.0	D
GERP RS		3.5
Varity_R		0.80
gMVP		0.97
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs369276986; hg19: chr7-20824140;