17-63909889-T-C

Variant names:

• chr17-63909889-T-C
• rs555182827
• NM_022579.3:c.491A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_022579.3(CSHL1):​c.491A>G​(p.His164Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000112 in 1,613,478 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: CSHL1 NM_022579.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.643

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.006618023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSHL1	NM_022579.3	c.491A>G	p.His164Arg	missense_variant	Exon 5 of 5	ENST00000309894.6	NP_072101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSHL1	ENST00000309894.6	c.491A>G	p.His164Arg	missense_variant	Exon 5 of 5	5	NM_022579.3	ENSP00000309524.5

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000115 AC: 29 AN: 251168 Hom.: 0 AF XY: 0.0000884 AC XY: 12 AN XY: 135740

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000773 AC: 113 AN: 1461184 Hom.: 0 Cov.: 33 AF XY: 0.0000784 AC XY: 57 AN XY: 726918

Gnomad4 AFR exome AF: 0.000986

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74484

Gnomad4 AFR AF: 0.00149

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000191 Hom.: 0

Bravo AF: 0.000476

ExAC AF: 0.000181 AC: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 17, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.491A>G (p.H164R) alteration is located in exon 5 (coding exon 5) of the CSHL1 gene. This alteration results from a A to G substitution at nucleotide position 491, causing the histidine (H) at amino acid position 164 to be replaced by an arginine (R). 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	0.066
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.28
DEOGEN2	Benign	0.050	.;.;.;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	T;T;T;T;T
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.0066	T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.69	.;.;.;.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.080	N;.;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.10	T;.;T;T;T
Sift4G	Benign	0.071	T;T;T;T;T
Polyphen		0.0	.;.;B;B;B
Vest4		0.029
MVP		0.38
MPC		0.026
ClinPred		0.016	T
GERP RS		0.24
Varity_R		0.036
gMVP		0.24

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

Other links and lift over

dbSNP: rs555182827; hg19: chr17-61987249;