rs1233560

Positions:

• chr7-155800744-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000193.4(SHH):​c.*2156C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.547 in 434,690 control chromosomes in the GnomAD database, including 67,412 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.50 (19951 hom., cov: 32)
  • Exomes 𝑓: 0.57 (47461 hom.)
• Consequence: SHH NM_000193.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.52

Genes affected

SHH (HGNC:10848): (sonic hedgehog signaling molecule) This gene encodes a protein that is instrumental in patterning the early embryo. It has been implicated as the key inductive signal in patterning of the ventral neural tube, the anterior-posterior limb axis, and the ventral somites. Of three human proteins showing sequence and functional similarity to the sonic hedgehog protein of Drosophila, this protein is the most similar. The protein is made as a precursor that is autocatalytically cleaved; the N-terminal portion is soluble and contains the signalling activity while the C-terminal portion is involved in precursor processing. More importantly, the C-terminal product covalently attaches a cholesterol moiety to the N-terminal product, restricting the N-terminal product to the cell surface and preventing it from freely diffusing throughout the developing embryo. Defects in this protein or in its signalling pathway are a cause of holoprosencephaly (HPE), a disorder in which the developing forebrain fails to correctly separate into right and left hemispheres. HPE is manifested by facial deformities. It is also thought that mutations in this gene or in its signalling pathway may be responsible for VACTERL syndrome, which is characterized by vertebral defects, anal atresia, tracheoesophageal fistula with esophageal atresia, radial and renal dysplasia, cardiac anomalies, and limb abnormalities. Additionally, mutations in a long range enhancer located approximately 1 megabase upstream of this gene disrupt limb patterning and can result in preaxial polydactyly. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.*2156C>T		3_prime_UTR_variant	3/3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261	c.*2156C>T		3_prime_UTR_variant	3/3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-499C>T		intron_variant		1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-147C>T		intron_variant		1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-77C>T		intron_variant		1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75840 AN: 151840 Hom.: 19948 Cov.: 32

Gnomad AFR AF: 0.341

Gnomad AMI AF: 0.362

Gnomad AMR AF: 0.605

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.641

Gnomad FIN AF: 0.597

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.488

GnomAD4 exome AF: 0.572 AC: 161839 AN: 282732 Hom.: 47461 Cov.: 0 AF XY: 0.577 AC XY: 92476 AN XY: 160206

Gnomad4 AFR exome AF: 0.353

Gnomad4 AMR exome AF: 0.721

Gnomad4 ASJ exome AF: 0.570

Gnomad4 EAS exome AF: 0.744

Gnomad4 SAS exome AF: 0.627

Gnomad4 FIN exome AF: 0.594

Gnomad4 NFE exome AF: 0.529

Gnomad4 OTH exome AF: 0.545

GnomAD4 genome AF: 0.499 AC: 75854 AN: 151958 Hom.: 19951 Cov.: 32 AF XY: 0.507 AC XY: 37676 AN XY: 74250

Gnomad4 AFR AF: 0.340

Gnomad4 AMR AF: 0.606

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.747

Gnomad4 SAS AF: 0.641

Gnomad4 FIN AF: 0.597

Gnomad4 NFE AF: 0.527

Gnomad4 OTH AF: 0.487

Alfa AF: 0.522 Hom.: 13340

Bravo AF: 0.492

Asia WGS AF: 0.636 AC: 2213 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.71
DANN	Benign	0.54

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

Publications

LitVar

Other links and lift over

dbSNP: rs1233560; hg19: chr7-155593438;