17-63909805-C-T

Variant names:

• chr17-63909805-C-T
• rs145173950
• NM_022579.3:c.575G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022579.3(CSHL1):​c.575G>A​(p.Gly192Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,984 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G192W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CSHL1 NM_022579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50
• Publications: 1 publications found

Genes affected

CSHL1 (HGNC:2442): (chorionic somatomammotropin hormone like 1) The protein encoded by this gene is a member of the somatotropin/prolactin family of hormones which play an important role in growth control. The gene, along with four other related genes, is located at the growth hormone locus on chromosome 17 where they are interspersed 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. This particular family member is expressed in placental villi, although it was originally thought to be a pseudogene. In fact, alternative splicing suggests that the majority of the transcripts would be unable to express a secreted protein. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ENSG00000303015 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022579.3. 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
	CSHL1	NM_022579.3	MANE Select	c.575G>A	p.Gly192Glu	missense	Exon 5 of 5	NP_072101.1	Q14406-1
	CSHL1	NM_022581.3		c.506G>A	p.Gly169Glu	missense	Exon 5 of 5	NP_072103.1	Q14406-2
	CSHL1	NM_001321069.2		c.458G>A	p.Gly153Glu	missense	Exon 5 of 5	NP_001307998.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSHL1	ENST00000309894.6	TSL:5 MANE Select	c.575G>A	p.Gly192Glu	missense	Exon 5 of 5	ENSP00000309524.5	Q14406-1
	CSHL1	ENST00000259003.14	TSL:1	c.389G>A	p.Gly130Glu	missense	Exon 5 of 5	ENSP00000259003.10	A0A0B4J1R0
	CSHL1	ENST00000346606.10	TSL:1	c.293G>A	p.Gly98Glu	missense	Exon 4 of 4	ENSP00000316360.10	Q14406-4

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251346 AF XY: 0.00

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

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 AF: 0.00000342 AC: 5 AN: 1461730 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111898

Other (OTH) AF: 0.0000166 AC: 1 AN: 60378

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74442

African (AFR) AF: 0.000120 AC: 5 AN: 41536

American (AMR) AF: 0.00 AC: 0 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.56	N
PhyloP100		1.5
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.63
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.045	D
Polyphen		0.54	P
Vest4		0.25
MVP		0.89
MPC		0.21
ClinPred		0.48	T
GERP RS		3.6
Varity_R		0.46
gMVP		0.46
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs145173950; hg19: chr17-61987165;