7-155803019-G-T

Variant names:

• chr7-155803019-G-T
• rs104894048
• NM_000193.4:c.1270C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM5 PP2 BP4

The NM_000193.4(SHH):​c.1270C>A​(p.Pro424Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,393,362 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P424A) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (1 hom.)
• Consequence: SHH NM_000193.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.622
• Publications: 4 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: Uncertain_significance. The variant received 2 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-155803019-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 8888.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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=0.2947269).

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.1270C>A	p.Pro424Thr	missense	Exon 3 of 3	NP_000184.1	Q15465
	SHH	NM_001310462.2		c.302-2774C>A		intron	N/A	NP_001297391.1
	SHH	NR_132318.2		n.563-2352C>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.1270C>A	p.Pro424Thr	missense	Exon 3 of 3	ENSP00000297261.2	Q15465
	SHH	ENST00000430104.5	TSL:1	c.302-2774C>A		intron	N/A	ENSP00000396621.1	C9JC48
	SHH	ENST00000435425.1	TSL:1	n.302-2422C>A		intron	N/A	ENSP00000413871.1	F8WEH4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000370 AC: 7 AN: 189074 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1393362 Hom.: 1 Cov.: 35 AF XY: 0.00000722 AC XY: 5 AN XY: 692100

African (AFR) AF: 0.00 AC: 0 AN: 29678

American (AMR) AF: 0.00 AC: 0 AN: 37580

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24524

East Asian (EAS) AF: 0.00 AC: 0 AN: 33680

South Asian (SAS) AF: 0.000234 AC: 18 AN: 76988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4470

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079100

Other (OTH) AF: 0.00 AC: 0 AN: 57152

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000435 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	8.8
DANN	Benign	0.53
DEOGEN2	Pathogenic	0.81	D
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.38	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.29	T
MetaSVM	Uncertain	0.70	D
MutationAssessor	Benign	0.28	N
PhyloP100		0.62
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.32
Sift	Benign	0.052	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.71		Gain of helix (P = 0.0199)
MVP		0.58
ClinPred		0.032	T
GERP RS		-0.67
Varity_R		0.054
gMVP		0.20
Mutation Taster		=62/38	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: rs104894048; hg19: chr7-155595713;