17-63910248-T-C

Position:

• chr17-63910248-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_022579.3(CSHL1):​c.385A>G​(p.Thr129Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0006 in 1,614,004 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (6 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: CSHL1 NM_022579.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.994

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014443338).
• BP6: Variant 17-63910248-T-C is Benign according to our data. Variant chr17-63910248-T-C is described in ClinVar as [Benign]. Clinvar id is 730143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CSHL1	NM_022579.3	c.385A>G	p.Thr129Ala	missense_variant	4/5	ENST00000309894.6	NP_072101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CSHL1	ENST00000309894.6	c.385A>G	p.Thr129Ala	missense_variant	4/5	5	NM_022579.3	ENSP00000309524	P1

Frequencies

GnomAD3 genomes AF: 0.00308 AC: 469 AN: 152040 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000819 AC: 206 AN: 251422 Hom.: 1 AF XY: 0.000625 AC XY: 85 AN XY: 135904

Gnomad AFR exome AF: 0.0110

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000342 AC: 500 AN: 1461846 Hom.: 2 Cov.: 84 AF XY: 0.000309 AC XY: 225 AN XY: 727228

Gnomad4 AFR exome AF: 0.0118

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00308 AC: 469 AN: 152158 Hom.: 6 Cov.: 32 AF XY: 0.00312 AC XY: 232 AN XY: 74404

Gnomad4 AFR AF: 0.0108

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.00337

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000791 AC: 96

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	0.25
DANN	Benign	0.12
DEOGEN2	Benign	0.048	.;.;.;.;.;.;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.51	T;T;T;T;T;T;T
MetaRNN	Benign	0.014	T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.71	.;.;.;.;.;.;N
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.13	N;N;.;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;T;.;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	.;.;.;B;B;.;B
Vest4		0.14
MVP		0.23
MPC		0.024
ClinPred		0.0079	T
GERP RS		0.76
Varity_R		0.031
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61762514; hg19: chr17-61987608;