rs1233555

Variant names:

• chr7-155806606-C-T
• rs1233555
• NM_000193.4:c.301-49G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-155806606-C-T
• chr7-155806606-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000193.4(SHH):​c.301-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,609,018 control chromosomes in the GnomAD database, including 273,620 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (21090 hom., cov: 32)
  • Exomes 𝑓: 0.58 (252530 hom.)
• Consequence: SHH NM_000193.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.782
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-155806606-C-T is Benign according to our data. Variant chr7-155806606-C-T is described in ClinVar as Benign. ClinVar VariationId is 255495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.64 is higher than 0.05.

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.301-49G>A		intron	N/A	NP_000184.1	Q15465
	SHH	NM_001310462.2		c.40-49G>A		intron	N/A	NP_001297391.1
	SHH	NR_132318.2		n.301-49G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SHH	ENST00000297261.7	TSL:1 MANE Select	c.301-49G>A		intron	N/A	ENSP00000297261.2	Q15465
	SHH	ENST00000430104.5	TSL:1	c.40-49G>A		intron	N/A	ENSP00000396621.1	C9JC48
	SHH	ENST00000472308.1	TSL:1	n.480G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.492 AC: 74782 AN: 151938 Hom.: 21076 Cov.: 32

Gnomad AFR AF: 0.204

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.617

Gnomad ASJ AF: 0.522

Gnomad EAS AF: 0.608

Gnomad SAS AF: 0.659

Gnomad FIN AF: 0.687

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.584

Gnomad OTH AF: 0.508

GnomAD2 exomes AF: 0.591 AC: 144464 AN: 244498 AF XY: 0.597

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.699

Gnomad ASJ exome AF: 0.533

Gnomad EAS exome AF: 0.604

Gnomad FIN exome AF: 0.686

Gnomad NFE exome AF: 0.581

Gnomad OTH exome AF: 0.579

GnomAD4 exome AF: 0.583 AC: 849993 AN: 1456962 Hom.: 252530 Cov.: 35 AF XY: 0.585 AC XY: 423938 AN XY: 724860

African (AFR) AF: 0.189 AC: 6300 AN: 33418

American (AMR) AF: 0.689 AC: 30787 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13721 AN: 26124

East Asian (EAS) AF: 0.611 AC: 24265 AN: 39690

South Asian (SAS) AF: 0.654 AC: 56396 AN: 86188

European-Finnish (FIN) AF: 0.688 AC: 34725 AN: 50496

Middle Eastern (MID) AF: 0.481 AC: 2510 AN: 5218

European-Non Finnish (NFE) AF: 0.583 AC: 647319 AN: 1110890

Other (OTH) AF: 0.564 AC: 33970 AN: 60254

GnomAD4 genome AF: 0.492 AC: 74815 AN: 152056 Hom.: 21090 Cov.: 32 AF XY: 0.503 AC XY: 37373 AN XY: 74324

African (AFR) AF: 0.204 AC: 8470 AN: 41514

American (AMR) AF: 0.618 AC: 9438 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.522 AC: 1812 AN: 3468

East Asian (EAS) AF: 0.607 AC: 3118 AN: 5136

South Asian (SAS) AF: 0.659 AC: 3176 AN: 4818

European-Finnish (FIN) AF: 0.687 AC: 7269 AN: 10576

Middle Eastern (MID) AF: 0.490 AC: 144 AN: 294

European-Non Finnish (NFE) AF: 0.584 AC: 39663 AN: 67948

Other (OTH) AF: 0.510 AC: 1078 AN: 2112

Alfa AF: 0.530 Hom.: 9478

Bravo AF: 0.472

Asia WGS AF: 0.605 AC: 2105 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Holoprosencephaly 3 (1)
-	-	1	Microphthalmia, isolated, with coloboma 5 (1)
-	-	1	not specified (1)
-	-	1	Solitary median maxillary central incisor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.7
DANN	Benign	0.69
PhyloP100		-0.78
Mutation Taster		=100/0	polymorphism (auto)

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: rs1233555; hg19: chr7-155599300; COSMIC: COSV51918728;