NM_000193.4:c.*118_*123dupGAATAA

Variant names:

• chr7-155802776-A-ATTATTC
• rs9333636
• NM_000193.4:c.*118_*123dupGAATAA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000193.4(SHH):​c.*118_*123dupGAATAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.17 in 545,218 control chromosomes in the GnomAD database, including 9,742 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (3472 hom., cov: 26)
  • Exomes 𝑓: 0.15 (6270 hom.)
• Consequence: SHH NM_000193.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.820
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 7-155802776-A-ATTATTC is Benign according to our data. Variant chr7-155802776-A-ATTATTC is described in ClinVar as [Benign]. Clinvar id is 1259170.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4	c.*118_*123dupGAATAA		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.*118_*123dupGAATAA		3_prime_UTR_variant	Exon 3 of 3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2537_302-2532dupGAATAA		intron_variant	Intron 3 of 3	1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2185_302-2180dupGAATAA		intron_variant	Intron 3 of 4	1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2115_302-2110dupGAATAA		intron_variant	Intron 3 of 4	1		ENSP00000410546.1

Frequencies

GnomAD3 genomes AF: 0.211 AC: 31907 AN: 151520 Hom.: 3470 Cov.: 26

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.0286

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.234

Gnomad NFE AF: 0.208

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.155 AC: 60890 AN: 393578 Hom.: 6270 Cov.: 7 AF XY: 0.155 AC XY: 30845 AN XY: 198366

African (AFR) AF: 0.236 AC: 2198 AN: 9312

American (AMR) AF: 0.155 AC: 1264 AN: 8150

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 2194 AN: 10294

East Asian (EAS) AF: 0.0276 AC: 655 AN: 23692

South Asian (SAS) AF: 0.0553 AC: 708 AN: 12794

European-Finnish (FIN) AF: 0.177 AC: 4111 AN: 23164

Middle Eastern (MID) AF: 0.201 AC: 321 AN: 1600

European-Non Finnish (NFE) AF: 0.162 AC: 45770 AN: 282934

Other (OTH) AF: 0.170 AC: 3669 AN: 21638

GnomAD4 genome AF: 0.211 AC: 31930 AN: 151640 Hom.: 3472 Cov.: 26 AF XY: 0.206 AC XY: 15290 AN XY: 74104

African (AFR) AF: 0.269 AC: 11117 AN: 41274

American (AMR) AF: 0.171 AC: 2604 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3468

East Asian (EAS) AF: 0.0288 AC: 149 AN: 5166

South Asian (SAS) AF: 0.118 AC: 566 AN: 4804

European-Finnish (FIN) AF: 0.195 AC: 2046 AN: 10492

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.208 AC: 14109 AN: 67892

Other (OTH) AF: 0.222 AC: 467 AN: 2102

Alfa AF: 0.0628 Hom.: 90

Asia WGS AF: 0.0790 AC: 273 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 08, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9333636; hg19: chr7-155595470;