7-155803413-C-T

Variant names:

• chr7-155803413-C-T
• rs112055654
• NM_000193.4:c.876G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS1

The NM_000193.4(SHH):​c.876G>A​(p.Gly292Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,525,792 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SHH NM_000193.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 0.582
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 7-155803413-C-T is Benign according to our data. Variant chr7-155803413-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 65911.
• BP7: Synonymous conserved (PhyloP=0.582 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00105 (159/152148) while in subpopulation AFR AF = 0.00359 (149/41556). AF 95% confidence interval is 0.00312. There are 1 homozygotes in GnomAd4. There are 80 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.876G>A	p.Gly292Gly	synonymous	Exon 3 of 3	NP_000184.1	Q15465
	SHH	NM_001310462.2		c.301+2883G>A		intron	N/A	NP_001297391.1
	SHH	NR_132318.2		n.563-2746G>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.876G>A	p.Gly292Gly	synonymous	Exon 3 of 3	ENSP00000297261.2	Q15465
	SHH	ENST00000430104.5	TSL:1	c.301+2883G>A		intron	N/A	ENSP00000396621.1	C9JC48
	SHH	ENST00000435425.1	TSL:1	n.302-2816G>A		intron	N/A	ENSP00000413871.1	F8WEH4

Frequencies

GnomAD3 genomes AF: 0.00103 AC: 156 AN: 152036 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00352

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000206 AC: 25 AN: 121632 AF XY: 0.000149

Gnomad AFR exome AF: 0.00430

Gnomad AMR exome AF: 0.000168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000222

Gnomad OTH exome AF: 0.000266

GnomAD4 exome AF: 0.000106 AC: 145 AN: 1373644 Hom.: 0 Cov.: 35 AF XY: 0.0000782 AC XY: 53 AN XY: 677512

African (AFR) AF: 0.00378 AC: 113 AN: 29876

American (AMR) AF: 0.000200 AC: 7 AN: 35052

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24774

East Asian (EAS) AF: 0.00 AC: 0 AN: 34738

South Asian (SAS) AF: 0.00 AC: 0 AN: 78134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4350

European-Non Finnish (NFE) AF: 0.00000651 AC: 7 AN: 1074550

Other (OTH) AF: 0.000314 AC: 18 AN: 57302

GnomAD4 genome AF: 0.00105 AC: 159 AN: 152148 Hom.: 1 Cov.: 33 AF XY: 0.00108 AC XY: 80 AN XY: 74400

African (AFR) AF: 0.00359 AC: 149 AN: 41556

American (AMR) AF: 0.000392 AC: 6 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67940

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000348 Hom.: 0

Bravo AF: 0.00122

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	Holoprosencephaly 3 (2)
-	1	1	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.5
DANN	Benign	0.82
PhyloP100		0.58

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: rs112055654; hg19: chr7-155596107;