chr17-8121687-C-T

Variant names:

• chr17-8121687-C-T
• rs1261403625
• NM_001165967.2:c.577G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001165967.2(HES7):​c.577G>A​(p.Gly193Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000017 in 1,174,824 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G193D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00100
• Publications: 0 publications found

Genes affected

HES7 (HGNC:15977): (hes family bHLH transcription factor 7) This gene encodes a member of the hairy and enhancer of split family of bHLH transcription factors. The mouse ortholog of this gene is regulated by Notch signaling. The protein functions as a transcriptional repressor, and is implicated in correct patterning of the axial skeleton. A mutation in this gene has been shown to result in spondylocostal dysostosis. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

HES7 Gene-Disease associations (from GenCC):

• spondylocostal dysostosis 4, autosomal recessive

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• autosomal recessive spondylocostal dysostosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 4 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.76017 (below the threshold of 3.09). Trascript score misZ: -2.7124 (below the threshold of 3.09). GenCC associations: The gene is linked to spondylocostal dysostosis 4, autosomal recessive, autosomal recessive spondylocostal dysostosis.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18055972).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001165967.2. 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
	HES7	NM_001165967.2	MANE Select	c.577G>A	p.Gly193Ser	missense	Exon 4 of 4	NP_001159439.1	Q9BYE0-2
	HES7	NM_032580.4		c.562G>A	p.Gly188Ser	missense	Exon 4 of 4	NP_115969.2	Q9BYE0-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HES7	ENST00000541682.7	TSL:1 MANE Select	c.577G>A	p.Gly193Ser	missense	Exon 4 of 4	ENSP00000446205.2	Q9BYE0-2
	HES7	ENST00000317814.8	TSL:1	c.562G>A	p.Gly188Ser	missense	Exon 4 of 4	ENSP00000314774.4	Q9BYE0-1
	HES7	ENST00000577735.1	TSL:3	c.*117G>A		downstream_gene	N/A	ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000170 AC: 2 AN: 1174824 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 564578

African (AFR) AF: 0.00 AC: 0 AN: 23422

American (AMR) AF: 0.00 AC: 0 AN: 8988

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16146

East Asian (EAS) AF: 0.00 AC: 0 AN: 26988

South Asian (SAS) AF: 0.00 AC: 0 AN: 43382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3274

European-Non Finnish (NFE) AF: 0.00000205 AC: 2 AN: 977054

Other (OTH) AF: 0.00 AC: 0 AN: 48352

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.77	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.0010
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.19
Sift	Benign	0.75	T
Sift4G	Benign	0.46	T
Polyphen		0.23	B
Vest4		0.073
MutPred		0.21		Gain of glycosylation at G188 (P = 0.013)
MVP		0.67
MPC		1.8
ClinPred		0.47	T
GERP RS		3.1
Varity_R		0.062
gMVP		0.19
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1261403625; hg19: chr17-8025005;