rs148863769

chr7-155800141-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000430104.5(SHH):c.406G>A(p.Gly136Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000649 in 471,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/12 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: SHH ENST00000430104.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.956

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004433453).
• BP6: Variant 7-155800141-C-T is Benign according to our data. Variant chr7-155800141-C-T is described in ClinVar as [Benign]. Clinvar id is 586571.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr7-155800141-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00158 (241/152348) while in subpopulation AFR AF= 0.00556 (231/41582). AF 95% confidence interval is 0.00497. There are 0 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 241 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHH	NM_000193.4	c.*2759G>A		3_prime_UTR_variant	3/3	ENST00000297261.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHH	ENST00000430104.5	c.406G>A	p.Gly136Arg	missense_variant	4/4	1
SHH	ENST00000297261.7	c.*2759G>A		3_prime_UTR_variant	3/3	1	NM_000193.4	P1
SHH	ENST00000435425.1	c.*174G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1
SHH	ENST00000441114.5	c.*235G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	1

Frequencies

GnomAD3 genomes AF: 0.00158 AC: 241 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00557

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000325 AC: 49 AN: 150898 Hom.: 0 AF XY: 0.000260 AC XY: 21 AN XY: 80896

Gnomad AFR exome AF: 0.00514

Gnomad AMR exome AF: 0.000488

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000204 AC: 65 AN: 319242 Hom.: 0 Cov.: 0 AF XY: 0.000144 AC XY: 26 AN XY: 180304

Gnomad4 AFR exome AF: 0.00544

Gnomad4 AMR exome AF: 0.000476

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000251

Gnomad4 OTH exome AF: 0.0000691

GnomAD4 genome AF: 0.00158 AC: 241 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00172 AC XY: 128 AN XY: 74492

Gnomad4 AFR AF: 0.00556

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00153 Hom.: 0

Bravo AF: 0.00188

ExAC AF: 0.000261 AC: 6

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.39
Cadd	Benign	1.9
Dann	Benign	0.64
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.31	T
MetaRNN	Benign	0.0044	T
MetaSVM	Uncertain	0.72	D
MutationTaster	Benign	1.0	N
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.16
Sift	Benign	0.39	T
Sift4G	Uncertain	0.042	D
Polyphen		0.013	B
MutPred		0.48		Gain of MoRF binding (P = 0.0141);
MVP		0.66
ClinPred		0.0020	T
GERP RS		-2.6

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

LitVar

Other links and lift over

dbSNP: rs148863769; hg19: chr7-155592835;