7-155802776-A-ATTATTC

Position:

• chr7-155802776-A-ATTATTC

Variant summary

Our verdict is Benign. Variant got -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

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.*118_*123dupGAATAA		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.*118_*123dupGAATAA		3_prime_UTR_variant	3/3	1	NM_000193.4	ENSP00000297261.2
SHH	ENST00000430104.5	c.302-2537_302-2532dupGAATAA		intron_variant		1		ENSP00000396621.1
SHH	ENST00000435425.1	n.302-2185_302-2180dupGAATAA		intron_variant		1		ENSP00000413871.1
SHH	ENST00000441114.5	n.302-2115_302-2110dupGAATAA		intron_variant		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

Gnomad4 AFR exome AF: 0.236

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.213

Gnomad4 EAS exome AF: 0.0276

Gnomad4 SAS exome AF: 0.0553

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.162

Gnomad4 OTH exome AF: 0.170

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

Gnomad4 AFR AF: 0.269

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0288

Gnomad4 SAS AF: 0.118

Gnomad4 FIN AF: 0.195

Gnomad4 NFE AF: 0.208

Gnomad4 OTH AF: 0.222

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 08, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9333636; hg19: chr7-155595470;