rs104894047

Positions:

• chr7-155803420-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000193.4(SHH):​c.869G>A​(p.Gly290Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,529,318 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (18 hom.)
• Consequence: SHH NM_000193.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 U:1 B:6
• Conservation: PhyloP100: 0.804

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06371763).
• BP6: Variant 7-155803420-C-T is Benign according to our data. Variant chr7-155803420-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 8887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-155803420-C-T is described in Lovd as [Likely_benign]. Variant chr7-155803420-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00233 (354/152130) while in subpopulation EAS AF= 0.0343 (176/5134). AF 95% confidence interval is 0.0301. There are 7 homozygotes in gnomad4. There are 209 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 354 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHH	NM_000193.4	c.869G>A	p.Gly290Asp	missense_variant	3/3	ENST00000297261.7	NP_000184.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7	c.869G>A	p.Gly290Asp	missense_variant	3/3	1	NM_000193.4	ENSP00000297261	P1
SHH	ENST00000430104.5	c.301+2876G>A		intron_variant		1		ENSP00000396621
SHH	ENST00000435425.1	c.302-2823G>A		intron_variant, NMD_transcript_variant		1		ENSP00000413871
SHH	ENST00000441114.5	c.302-2753G>A		intron_variant, NMD_transcript_variant		1		ENSP00000410546

Frequencies

GnomAD3 genomes AF: 0.00233 AC: 354 AN: 152020 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.0342

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00897

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.00331 AC: 414 AN: 125120 Hom.: 6 AF XY: 0.00309 AC XY: 213 AN XY: 68864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000415

Gnomad ASJ exome AF: 0.00357

Gnomad EAS exome AF: 0.0308

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.00672

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.00181

GnomAD4 exome AF: 0.00112 AC: 1536 AN: 1377188 Hom.: 18 Cov.: 35 AF XY: 0.00108 AC XY: 737 AN XY: 679334

Gnomad4 AFR exome AF: 0.000132

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.00353

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.00138

Gnomad4 FIN exome AF: 0.00747

Gnomad4 NFE exome AF: 0.000111

Gnomad4 OTH exome AF: 0.00235

GnomAD4 genome AF: 0.00233 AC: 354 AN: 152130 Hom.: 7 Cov.: 33 AF XY: 0.00281 AC XY: 209 AN XY: 74392

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.0343

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00897

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00174

ExAC AF: 0.00114 AC: 99

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Holoprosencephaly 3 Pathogenic:1 Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 29, 2013	- -
Uncertain significance, no assertion criteria provided	literature only	OMIM	May 01, 2010	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	This variant is associated with the following publications: (PMID: 32939873, 31180159, 20425842, 18655123, 10556296, 19533790) -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 20, 2014

- -

SHH-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Schizencephaly;C1840235:Solitary median maxillary central incisor syndrome;C1840529:Holoprosencephaly 3;C1968843:Microphthalmia, isolated, with coloboma 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	8.7
DANN	Benign	0.77
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.064	T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	4.2e-12	A
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.47	N
REVEL	Uncertain	0.59
Sift	Benign	0.21	T
Sift4G	Benign	0.27	T
Polyphen		0.55	P
Vest4		0.68
MVP		1.0
ClinPred		0.017	T
GERP RS		0.85
Varity_R		0.063
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894047; hg19: chr7-155596114;