chr7-155806606-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000472308.1(SHH):n.480G>A variant causes a non coding transcript exon 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
ENST00000472308.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.782

Publications

10 publications found

Variant links:

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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
microphthalmia, isolated, with coloboma 5
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia
polydactyly of a triphalangeal thumb
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
solitary median maxillary central incisor syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: G2P, Ambry Genetics
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

SHH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHH	NM_000193.4 link	c.301-49G>A		intron_variant	Intron 1 of 2	ENST00000297261.7	NP_000184.1	Q15465

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHH	ENST00000297261.7 link	c.301-49G>A		intron_variant	Intron 1 of 2	1	NM_000193.4	ENSP00000297261.2		Q15465

Frequencies

GnomAD3 genomes

AF:

0.492

AC:

74782

AN:

151938

Hom.:

21076

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.585

AC XY:

423938

AN XY:

724860

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

20095

40190

60285

80380

100475

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17786

35572

53358

71144

88930

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.492

AC:

74815

AN:

152056

Hom.:

21090

Cov.:

AF XY:

0.503

AC XY:

37373

AN XY:

74324

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1736

3472

5207

6943

8679

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

656

1312

1968

2624

3280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.530

Hom.:

9478

Bravo

AF:

0.472

Asia WGS

AF:

0.605

AC:

2105

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microphthalmia, isolated, with coloboma 5

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Solitary median maxillary central incisor syndrome

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Holoprosencephaly 3

Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.7

(source)

DANN

Benign

0.69

PhyloP100

-0.78

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over