17-63895497-C-G

Position:

• chr17-63895497-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001317.6(CSH1):​c.432G>C​(p.Glu144Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: CSH1 NM_001317.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSH1	NM_001317.6	c.432G>C	p.Glu144Asp	missense_variant	4/5	ENST00000316193.13	NP_001308.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSH1	ENST00000316193.13	c.432G>C	p.Glu144Asp	missense_variant	4/5	1	NM_001317.6	ENSP00000316416.8

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000756

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

Jul 28, 2021

The c.432G>C (p.E144D) alteration is located in exon 4 (coding exon 4) of the CSH1 gene. This alteration results from a G to C substitution at nucleotide position 432, causing the glutamic acid (E) at amino acid position 144 to be replaced by an aspartic acid (D). 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;D;T
Eigen	Benign	-0.058
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.55	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	0.37	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	0.99	D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-2.5	N;N;.
REVEL	Uncertain	0.53
Sift	Benign	0.043	D;D;.
Sift4G	Uncertain	0.028	D;D;D
Polyphen		0.74	.;P;.
Vest4		0.48
MutPred		0.67		Loss of ubiquitination at K141 (P = 0.1601);Loss of ubiquitination at K141 (P = 0.1601);.;
MVP		0.38
MPC		1.7
ClinPred		0.94	D
GERP RS		0.43
Varity_R		0.30
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1349539704; hg19: chr17-61972857;