Genetic Variant SHH:p.Leu360Leu (chr7-155803211-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BS1BS2

The NM_000193.4(SHH):c.1078C>T(p.Leu360Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00168 in 1,509,260 control chromosomes in the GnomAD database, including 7 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 0.00074 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 7 hom. )

Consequence

SHH
NM_000193.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.22

Publications

1 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
microphthalmia, isolated, with coloboma 5
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
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

new If you want to explore the variant's impact on the transcript NM_000193.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 7-155803211-G-A is Benign according to our data. Variant chr7-155803211-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196230.

BP7

Synonymous conserved (PhyloP=1.22 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000743 (113/152016) while in subpopulation NFE AF = 0.00141 (96/67954). AF 95% confidence interval is 0.00118. There are 0 homozygotes in GnomAd4. There are 53 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHH	NM_000193.4	MANE Select	c.1078C>T	p.Leu360Leu	synonymous	Exon 3 of 3	NP_000184.1	Q15465
SHH	NM_001310462.2		c.302-2966C>T		intron	N/A	NP_001297391.1
SHH	NR_132318.2		n.563-2544C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHH	ENST00000297261.7	TSL:1 MANE Select	c.1078C>T	p.Leu360Leu	synonymous	Exon 3 of 3	ENSP00000297261.2	Q15465
SHH	ENST00000430104.5	TSL:1	c.302-2966C>T		intron	N/A	ENSP00000396621.1	C9JC48
SHH	ENST00000435425.1	TSL:1	n.302-2614C>T		intron	N/A	ENSP00000413871.1	F8WEH4

Frequencies

GnomAD3 genomes

AF:

0.000750

AC:

114

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00141

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000513

AC:

AN:

118886

AF XY:

0.000562

show subpopulations

Gnomad AFR exome

AF:

0.000501

Gnomad AMR exome

AF:

0.000287

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000950

Gnomad OTH exome

AF:

0.000662

GnomAD4 exome

AF:

0.00178

AC:

2421

AN:

1357244

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

1172

AN XY:

671474

show subpopulations

African (AFR)

AF:

0.000353

AC:

AN:

28290

American (AMR)

AF:

0.000372

AC:

AN:

32268

Ashkenazi Jewish (ASJ)

AF:

0.0000419

AC:

AN:

23860

East Asian (EAS)

AF:

0.00

AC:

AN:

30922

South Asian (SAS)

AF:

0.000225

AC:

AN:

75440

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5486

European-Non Finnish (NFE)

AF:

0.00217

AC:

2316

AN:

1066578

Other (OTH)

AF:

0.00116

AC:

AN:

56248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

154

307

461

614

768

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

224

336

448

560

<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:

0.000743

AC:

113

AN:

152016

Hom.:

Cov.:

AF XY:

0.000713

AC XY:

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.000313

AC:

AN:

41524

American (AMR)

AF:

0.000131

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10488

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00141

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00134

Hom.:

Bravo

AF:

0.000763

Asia WGS

AF:

0.000294

AC:

AN:

3420

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Holoprosencephaly 3 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

9.5

(source)

DANN

Uncertain

0.98

PhyloP100

1.2

Mutation Taster

=100/0

polymorphism

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over