7-155803108-C-A

Variant names:

• chr7-155803108-C-A
• rs551809680
• NM_000193.4:c.1181G>T

Variant summary

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

The NM_000193.4(SHH):​c.1181G>T​(p.Arg394Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,195,906 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R394H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000025 (0 hom.)
• Consequence: SHH NM_000193.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.106
• Publications: 2 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: 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 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.9479 (below the threshold of 3.09). Trascript score misZ: 0.49525 (below the threshold of 3.09). GenCC associations: The gene is linked to polydactyly of a triphalangeal thumb, microphthalmia, isolated, with coloboma 5, solitary median maxillary central incisor syndrome, holoprosencephaly 3, skeletal system disorder, hypoplastic tibiae-postaxial polydactyly syndrome, holoprosencephaly, syndactyly type 4, microphthalmia, isolated, with coloboma, autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome, triphalangeal thumb-polysyndactyly syndrome.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.1181G>T	p.Arg394Leu	missense_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.1181G>T	p.Arg394Leu	missense_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2863G>T		intron_variant	Intron 3 of 3	1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2511G>T		intron_variant	Intron 3 of 4	1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2441G>T		intron_variant	Intron 3 of 4	1		ENSP00000410546.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 25356 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00000251 AC: 3 AN: 1195906 Hom.: 0 Cov.: 35 AF XY: 0.00000172 AC XY: 1 AN XY: 580868

African (AFR) AF: 0.0000416 AC: 1 AN: 24044

American (AMR) AF: 0.00 AC: 0 AN: 11654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17026

East Asian (EAS) AF: 0.00 AC: 0 AN: 26914

South Asian (SAS) AF: 0.00 AC: 0 AN: 42780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4024

European-Non Finnish (NFE) AF: 0.00000203 AC: 2 AN: 983772

Other (OTH) AF: 0.00 AC: 0 AN: 48654

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1181G>T (p.R394L) alteration is located in exon 3 (coding exon 3) of the SHH gene. This alteration results from a G to T substitution at nucleotide position 1181, causing the arginine (R) at amino acid position 394 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.094	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Uncertain	0.77	D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	2.0	M
PhyloP100		0.11
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.82	N
REVEL	Uncertain	0.41
Sift	Benign	0.83	T
Sift4G	Benign	0.35	T
Polyphen		0.042	B
Vest4		0.079
MutPred		0.84		Loss of disorder (P = 0.0471);
MVP		0.92
ClinPred		0.41	T
GERP RS		2.6
Varity_R		0.14
gMVP		0.32
Mutation Taster		=63/37	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: rs551809680; hg19: chr7-155595802;