rs104894051

Variant names:

• chr7-155803523-C-A
• rs104894051
• NM_000193.4:c.766G>T

Your query was ambiguous. Multiple possible variants found:

• chr7-155803523-C-A
• chr7-155803523-C-G
• chr7-155803523-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000193.4(SHH):​c.766G>T​(p.Glu256*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000696 in 1,435,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SHH NM_000193.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 4.32
• Publications: 3 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: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• microphthalmia, isolated, with coloboma 5

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• polydactyly of a triphalangeal thumb

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

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, G2P
• 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 49 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-155803523-C-A is Pathogenic according to our data. Variant chr7-155803523-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 8893.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000193.4. 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
	SHH	NM_000193.4	MANE Select	c.766G>T	p.Glu256*	stop_gained	Exon 3 of 3	NP_000184.1	Q15465
	SHH	NM_001310462.2		c.301+2773G>T		intron	N/A	NP_001297391.1
	SHH	NR_132318.2		n.562+2773G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHH	ENST00000297261.7	TSL:1 MANE Select	c.766G>T	p.Glu256*	stop_gained	Exon 3 of 3	ENSP00000297261.2	Q15465
	SHH	ENST00000430104.5	TSL:1	c.301+2773G>T		intron	N/A	ENSP00000396621.1	C9JC48
	SHH	ENST00000435425.1	TSL:1	n.301+2773G>T		intron	N/A	ENSP00000413871.1	F8WEH4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1435948 Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1 AN XY: 713342

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33244

American (AMR) AF: 0.00 AC: 0 AN: 43000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39094

South Asian (SAS) AF: 0.00 AC: 0 AN: 84150

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105012

Other (OTH) AF: 0.00 AC: 0 AN: 59658

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
2	-	-	Holoprosencephaly 3 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	39
DANN	Uncertain	0.99
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.3
Vest4		0.92
GERP RS		3.3
Mutation Taster		=9/191	disease causing (ClinVar)

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: rs104894051; hg19: chr7-155596217;