Genetic Variant NM_022579.3:c.494T>A (chr17-63909886-A-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_022579.3(CSHL1):c.494T>A(p.Leu165Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L165R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

CSHL1
NM_022579.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.162

Publications

2 publications found

Variant links:

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]

CSHL1 links:

ENSG00000303015 (HGNC:):

ENSG00000303015 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05317235).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSHL1	NM_022579.3	MANE Select	c.494T>A	p.Leu165Gln	missense	Exon 5 of 5	NP_072101.1	Q14406-1
CSHL1	NM_022581.3		c.425T>A	p.Leu142Gln	missense	Exon 5 of 5	NP_072103.1	Q14406-2
CSHL1	NM_001321069.2		c.377T>A	p.Leu126Gln	missense	Exon 5 of 5	NP_001307998.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CSHL1	ENST00000309894.6	TSL:5 MANE Select	c.494T>A	p.Leu165Gln	missense	Exon 5 of 5	ENSP00000309524.5	Q14406-1
CSHL1	ENST00000259003.14	TSL:1	c.308T>A	p.Leu103Gln	missense	Exon 5 of 5	ENSP00000259003.10	A0A0B4J1R0
CSHL1	ENST00000346606.10	TSL:1	c.212T>A	p.Leu71Gln	missense	Exon 4 of 4	ENSP00000316360.10	Q14406-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251164

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

3.0

(source)

DANN

Benign

0.26

DEOGEN2

Benign

0.12

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0089

LIST_S2

Benign

0.67

M_CAP

Benign

0.037

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.81

MutationAssessor

Benign

-1.1

PhyloP100

0.16

PrimateAI

Benign

0.24

PROVEAN

Benign

3.1

REVEL

Benign

0.20

Sift

Benign

0.18

Sift4G

Benign

0.25

Polyphen

0.0

Vest4

0.15

MutPred

0.49

Gain of disorder (P = 0.0521)

MVP

0.14

MPC

0.024

ClinPred

0.55

GERP RS

-0.20

Varity_R

0.083

gMVP

0.42

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over