Variant 17-63896135-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001317.6(CSH1):c.111C>A(p.Asp37Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 5)

Exomes 𝑓: 0.00015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CSH1
NM_001317.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.05

Variant links:

Genes affected

CSH1 (HGNC:2440): (chorionic somatomammotropin hormone 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones and plays an important role in growth control. The gene is located at the growth hormone locus on chromosome 17 along with four other related genes in the same transcriptional orientation; an arrangement which is thought to have evolved by a series of gene duplications. Although the five genes share a remarkably high degree of sequence identity, they are expressed selectively in different tissues. Alternative splicing generates additional isoforms of each of the five growth hormones, leading to further diversity and potential for specialization. This particular family member is expressed mainly in the placenta and utilizes multiple transcription initiation sites. Expression of the identical mature proteins for chorionic somatomammotropin hormones 1 and 2 is upregulated during development, although the ratio of 1 to 2 increases by term. Mutations in this gene result in placental lactogen deficiency and Silver-Russell syndrome. [provided by RefSeq, Jul 2008]

CSH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.025169969).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSH1	NM_001317.6 linkuse as main transcript	c.111C>A	p.Asp37Glu	missense_variant	2/5	ENST00000316193.13	NP_001308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSH1	ENST00000316193.13 linkuse as main transcript	c.111C>A	p.Asp37Glu	missense_variant	2/5	1	NM_001317.6	ENSP00000316416	P1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

29956

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00718

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000257

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000153

AC:

106

AN:

690610

Hom.:

Cov.:

AF XY:

0.000116

AC XY:

AN XY:

353100

show subpopulations

Gnomad4 AFR exome

AF:

0.00562

Gnomad4 AMR exome

AF:

0.000340

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000573

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000204

Gnomad4 OTH exome

AF:

0.000306

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000802

AC:

AN:

29936

Hom.:

Cov.:

AF XY:

0.000698

AC XY:

AN XY:

14328

show subpopulations

Gnomad4 AFR

AF:

0.00717

Gnomad4 AMR

AF:

0.000257

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.111C>A (p.D37E) alteration is located in exon 2 (coding exon 2) of the CSH1 gene. This alteration results from a C to A substitution at nucleotide position 111, causing the aspartic acid (D) at amino acid position 37 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

2.1

DANN

Benign

0.96

DEOGEN2

Benign

0.30

T;D;D

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.54

T;T;T

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.025

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.3

.;L;.

MutationTaster

Benign

1.0

D;N;N;N

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.081

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.66

T;T;T

Polyphen

0.041

B;.;B

Vest4

0.043

MutPred

0.48

Gain of disorder (P = 0.2344);Gain of disorder (P = 0.2344);Gain of disorder (P = 0.2344);

MVP

0.16

MPC

1.0

ClinPred

0.073

GERP RS

1.6

Varity_R

0.14

gMVP

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over