chr7-155803420-C-T

Variant names:

• chr7-155803420-C-T
• rs104894047
• NM_000193.4:c.869G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 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. 12/21 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:7
• Conservation: PhyloP100: 0.804
• Publications: 12 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 -19 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 26 curated pathogenic missense variants (we use a threshold of 10). The gene has 8 curated benign missense variants. Gene score misZ: 2.9479 (below the threshold of 3.09). Trascript score misZ: 0.49525 (below the threshold of 3.09). GenCC associations: The gene is linked to polydactyly of a triphalangeal thumb, microphthalmia, isolated, with coloboma 5, solitary median maxillary central incisor syndrome, holoprosencephaly 3, skeletal system disorder, hypoplastic tibiae-postaxial polydactyly syndrome, holoprosencephaly, syndactyly type 4, microphthalmia, isolated, with coloboma, autosomal dominant preaxial polydactyly-upperback hypertrichosis syndrome, triphalangeal thumb-polysyndactyly syndrome.
• 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 Benign/Likely_benign. ClinVar VariationId is 8887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AD,AR gene

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.869G>A	p.Gly290Asp	missense	Exon 3 of 3	NP_000184.1	Q15465
	SHH	NM_001310462.2		c.301+2876G>A		intron	N/A	NP_001297391.1
	SHH	NR_132318.2		n.563-2753G>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.869G>A	p.Gly290Asp	missense	Exon 3 of 3	ENSP00000297261.2	Q15465
	SHH	ENST00000430104.5	TSL:1	c.301+2876G>A		intron	N/A	ENSP00000396621.1	C9JC48
	SHH	ENST00000435425.1	TSL:1	n.302-2823G>A		intron	N/A	ENSP00000413871.1	F8WEH4

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

GnomAD2 exomes AF: 0.00331 AC: 414 AN: 125120 AF XY: 0.00309

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 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

African (AFR) AF: 0.000132 AC: 4 AN: 30418

American (AMR) AF: 0.000113 AC: 4 AN: 35382

Ashkenazi Jewish (ASJ) AF: 0.00353 AC: 88 AN: 24914

East Asian (EAS) AF: 0.0232 AC: 812 AN: 35054

South Asian (SAS) AF: 0.00138 AC: 108 AN: 78490

European-Finnish (FIN) AF: 0.00747 AC: 264 AN: 35326

Middle Eastern (MID) AF: 0.000450 AC: 2 AN: 4448

European-Non Finnish (NFE) AF: 0.000111 AC: 119 AN: 1075730

Other (OTH) AF: 0.00235 AC: 135 AN: 57426

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

African (AFR) AF: 0.000746 AC: 31 AN: 41548

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 13 AN: 3472

East Asian (EAS) AF: 0.0343 AC: 176 AN: 5134

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00897 AC: 95 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 67950

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00174

ExAC AF: 0.00114 AC: 99

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	1	1	Holoprosencephaly 3 (3)
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Schizencephaly;C1840235:Solitary median maxillary central incisor syndrome;C1840529:Holoprosencephaly 3;C1968843:Microphthalmia, isolated, with coloboma 5 (1)
-	-	1	SHH-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.80
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
Mutation Taster		=91/9	polymorphism

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: rs104894047; hg19: chr7-155596114;