17-63896134-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001317.6(CSH1):c.112C>G(p.His38Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H38Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00073 ( 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: 1.33

Publications

0 publications found

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:

ENSG00000303015 (HGNC:):

ENSG00000303015 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07429439).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317.6. 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
	CSH1	NM_001317.6	MANE Select	c.112C>G	p.His38Asp	missense	Exon 2 of 5	NP_001308.1	P0DML2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSH1	ENST00000316193.13	TSL:1 MANE Select	c.112C>G	p.His38Asp	missense	Exon 2 of 5	ENSP00000316416.8	P0DML2
CSH1	ENST00000329882.8	TSL:2	c.112C>G	p.His38Asp	missense	Exon 2 of 4	ENSP00000333268.8	A6NFB4
CSH1	ENST00000453363.7	TSL:5	c.112C>G	p.His38Asp	missense	Exon 2 of 3	ENSP00000402517.2	B1A4H2

Frequencies

GnomAD3 genomes

AF:

0.000732

AC:

AN:

30068

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00651

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000255

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

GnomAD2 exomes

AF:

0.0000124

AC:

AN:

160674

AF XY:

0.0000115

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000796

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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000147

AC:

102

AN:

692246

Hom.:

Cov.:

AF XY:

0.000110

AC XY:

AN XY:

353942

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00530

AC:

AN:

13212

American (AMR)

AF:

0.000339

AC:

AN:

23600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14324

East Asian (EAS)

AF:

0.00

AC:

AN:

29110

South Asian (SAS)

AF:

0.0000572

AC:

AN:

52444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

33642

Middle Eastern (MID)

AF:

0.000432

AC:

AN:

2316

European-Non Finnish (NFE)

AF:

0.0000204

AC:

AN:

490922

Other (OTH)

AF:

0.000306

AC:

AN:

32676

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.292

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000732

AC:

AN:

30050

Hom.:

Cov.:

AF XY:

0.000696

AC XY:

AN XY:

14364

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00650

AC:

AN:

3230

American (AMR)

AF:

0.000255

AC:

AN:

3916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

510

East Asian (EAS)

AF:

0.00

AC:

AN:

778

South Asian (SAS)

AF:

0.00

AC:

AN:

1200

European-Finnish (FIN)

AF:

0.00

AC:

AN:

2900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

16868

Other (OTH)

AF:

0.00

AC:

AN:

376

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000000184369), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.343

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:

0.000144

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Benign

-0.27

CADD

Benign

8.4

(source)

DANN

Benign

0.57

DEOGEN2

Benign

0.23

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.42

M_CAP

Uncertain

0.15

MetaRNN

Benign

0.074

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.57

PhyloP100

1.3

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.78

REVEL

Uncertain

0.32

Sift

Benign

0.18

Sift4G

Benign

0.33

Polyphen

0.0

Vest4

0.27

MutPred

0.61

Loss of catalytic residue at M40 (P = 0.0241)

MVP

0.75

MPC

1.4

ClinPred

0.081

GERP RS

0.32

PromoterAI

0.046

Neutral

(source)

Varity_R

0.10

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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