chr7-20784367-C-T

Variant names:

• chr7-20784367-C-T
• rs2128063117
• NM_182700.6:c.1450G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.200
• 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: 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.: 32

GnomAD4 exome AF: 0.00000146 AC: 2 AN: 1372568 Hom.: 0 Cov.: 37 AF XY: 0.00000295 AC XY: 2 AN XY: 677182

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

African (AFR) AF: 0.0000335 AC: 1 AN: 29810

American (AMR) AF: 0.00 AC: 0 AN: 35018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24842

East Asian (EAS) AF: 0.00 AC: 0 AN: 34806

South Asian (SAS) AF: 0.00 AC: 0 AN: 78074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4052

European-Non Finnish (NFE) AF: 9.30e-7 AC: 1 AN: 1074854

Other (OTH) AF: 0.00 AC: 0 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.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.042	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
PhyloP100		-0.20
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.065
Sift	Benign	0.48	T
Sift4G	Benign	0.58	T
Polyphen		0.14	B
Vest4		0.12
MutPred		0.33		Gain of glycosylation at A466 (P = 0.0118)
MVP		0.11
ClinPred		0.21	T
GERP RS		3.7
Varity_R		0.074
gMVP		0.50
Mutation Taster		=82/18	polymorphism

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: rs2128063117; hg19: chr7-20823986;