17-8122394-A-C

Variant names:

• chr17-8122394-A-C
• rs1348325
• NM_001165967.2:c.175T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Strong

The NM_001165967.2(HES7):​c.175T>G​(p.Leu59Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L59L) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.78
• Publications: 11 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: Likely_pathogenic. The variant received 7 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 autosomal recessive spondylocostal dysostosis, spondylocostal dysostosis 4, autosomal recessive.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

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.175T>G	p.Leu59Val	missense	Exon 3 of 4	NP_001159439.1	Q9BYE0-2
	HES7	NM_032580.4		c.175T>G	p.Leu59Val	missense	Exon 3 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.175T>G	p.Leu59Val	missense	Exon 3 of 4	ENSP00000446205.2	Q9BYE0-2
	HES7	ENST00000317814.8	TSL:1	c.175T>G	p.Leu59Val	missense	Exon 3 of 4	ENSP00000314774.4	Q9BYE0-1
	HES7	ENST00000577735.1	TSL:3	c.151T>G	p.Leu51Val	missense	Exon 4 of 5	ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000461 AC: 1 AN: 217058 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000316

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 6.92e-7 AC: 1 AN: 1445046 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 717074

African (AFR) AF: 0.00 AC: 0 AN: 33096

American (AMR) AF: 0.0000236 AC: 1 AN: 42444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25696

East Asian (EAS) AF: 0.00 AC: 0 AN: 38998

South Asian (SAS) AF: 0.00 AC: 0 AN: 83270

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104140

Other (OTH) AF: 0.00 AC: 0 AN: 59724

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.60	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		1.8
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.0	D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.87		Gain of methylation at K55 (P = 0.1286)
MVP		0.89
MPC		1.8
ClinPred		0.99	D
GERP RS		3.2
Varity_R		0.85
gMVP		0.71
Mutation Taster		=86/14	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: rs1348325; hg19: chr17-8025712;