17-63896132-G-C

Position:

• chr17-63896132-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001317.6(CSH1):​c.114C>G​(p.His38Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 5)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CSH1 NM_001317.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.394

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09528282).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSH1	NM_001317.6	c.114C>G	p.His38Gln	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	c.114C>G	p.His38Gln	missense_variant	2/5	1	NM_001317.6	ENSP00000316416	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 17 AN: 30220 Hom.: 0 Cov.: 5 FAILED QC

Gnomad AFR AF: 0.00494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00260

GnomAD3 exomes AF: 0.0000125 AC: 2 AN: 159914 Hom.: 0 AF XY: 0.0000116 AC XY: 1 AN XY: 86320

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000798

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000129 AC: 90 AN: 697010 Hom.: 0 Cov.: 9 AF XY: 0.000101 AC XY: 36 AN XY: 356342

Gnomad4 AFR exome AF: 0.00453

Gnomad4 AMR exome AF: 0.000296

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000570

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.000273

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000563 AC: 17 AN: 30210 Hom.: 0 Cov.: 5 AF XY: 0.000554 AC XY: 8 AN XY: 14436

Gnomad4 AFR AF: 0.00492

Gnomad4 AMR AF: 0.00

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: 0.00260

Alfa AF: 0.0000960 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.114C>G (p.H38Q) alteration is located in exon 2 (coding exon 2) of the CSH1 gene. This alteration results from a C to G substitution at nucleotide position 114, causing the histidine (H) at amino acid position 38 to be replaced by a glutamine (Q). 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	0.15
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	5.9
DANN	Benign	0.60
DEOGEN2	Benign	0.29	T;D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.77	T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.5	.;L;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.6	N;N;N
REVEL	Benign	0.20
Sift	Uncertain	0.0090	D;D;D
Sift4G	Uncertain	0.017	D;D;D
Polyphen		0.13	B;.;B
Vest4		0.17
MutPred		0.61		Loss of catalytic residue at M40 (P = 0.018);Loss of catalytic residue at M40 (P = 0.018);Loss of catalytic residue at M40 (P = 0.018);
MVP		0.35
MPC		1.2
ClinPred		0.10	T
GERP RS		-0.70
Varity_R		0.27
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs747146179; hg19: chr17-61973492;