rs1233560

Variant names:

• chr7-155800744-G-A
• rs1233560
• NM_000193.4:c.*2156C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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]

SHH Gene-Disease associations (from GenCC):

• holoprosencephaly 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• microphthalmia, isolated, with coloboma 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
• polydactyly of a triphalangeal thumb

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
• solitary median maxillary central incisor syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
• skeletal system disorder

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypoplastic tibiae-postaxial polydactyly syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• microphthalmia, isolated, with coloboma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• syndactyly type 4

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• triphalangeal thumb-polysyndactyly syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• holoprosencephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.*2156C>T		3_prime_UTR_variant	Exon 3 of 3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7	c.*2156C>T		3_prime_UTR_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-499C>T		intron_variant	Intron 3 of 3	1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-147C>T		intron_variant	Intron 3 of 4	1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-77C>T		intron_variant	Intron 3 of 4	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

African (AFR) AF: 0.353 AC: 2625 AN: 7436

American (AMR) AF: 0.721 AC: 17494 AN: 24260

Ashkenazi Jewish (ASJ) AF: 0.570 AC: 5024 AN: 8808

East Asian (EAS) AF: 0.744 AC: 6755 AN: 9076

South Asian (SAS) AF: 0.627 AC: 34858 AN: 55616

European-Finnish (FIN) AF: 0.594 AC: 9299 AN: 15648

Middle Eastern (MID) AF: 0.490 AC: 1282 AN: 2616

European-Non Finnish (NFE) AF: 0.529 AC: 77414 AN: 146278

Other (OTH) AF: 0.545 AC: 7088 AN: 12994

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

African (AFR) AF: 0.340 AC: 14086 AN: 41434

American (AMR) AF: 0.606 AC: 9255 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1946 AN: 3468

East Asian (EAS) AF: 0.747 AC: 3838 AN: 5136

South Asian (SAS) AF: 0.641 AC: 3084 AN: 4810

European-Finnish (FIN) AF: 0.597 AC: 6304 AN: 10556

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35842 AN: 67952

Other (OTH) AF: 0.487 AC: 1029 AN: 2112

Alfa AF: 0.523 Hom.: 22286

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
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs1233560; hg19: chr7-155593438;