17-8121583-T-G

Variant names:

• chr17-8121583-T-G
• rs575817248
• NM_001165967.2:c.681A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001165967.2(HES7):​c.681A>C​(p.Arg227Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000305 in 1,309,760 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: HES7 NM_001165967.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.259
• 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 3 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.

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.681A>C	p.Arg227Ser	missense	Exon 4 of 4	NP_001159439.1	Q9BYE0-2
	HES7	NM_032580.4		c.666A>C	p.Arg222Ser	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.681A>C	p.Arg227Ser	missense	Exon 4 of 4	ENSP00000446205.2	Q9BYE0-2
	HES7	ENST00000317814.8	TSL:1	c.666A>C	p.Arg222Ser	missense	Exon 4 of 4	ENSP00000314774.4	Q9BYE0-1
	HES7	ENST00000577735.1	TSL:3	c.*221A>C		downstream_gene	N/A	ENSP00000462491.1	J3KSH6

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151810 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000259 AC: 3 AN: 1157842 Hom.: 0 Cov.: 30 AF XY: 0.00000180 AC XY: 1 AN XY: 554370

African (AFR) AF: 0.00 AC: 0 AN: 23282

American (AMR) AF: 0.00 AC: 0 AN: 8786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15852

East Asian (EAS) AF: 0.00 AC: 0 AN: 26884

South Asian (SAS) AF: 0.0000800 AC: 3 AN: 37494

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26084

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3226

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 968644

Other (OTH) AF: 0.00 AC: 0 AN: 47590

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151918 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67880

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.091
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.26
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.63
MutPred		0.48		Gain of glycosylation at R222 (P = 0.0093)
MVP		0.99
MPC		0.83
ClinPred		0.92	D
GERP RS		4.0
Varity_R		0.82
gMVP		0.65
Mutation Taster		=77/23	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: rs575817248; hg19: chr17-8024901;