17-63910441-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_001318.4(CSHL1):​c.3G>C​(p.Met1?) variant causes a start lost 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

CSHL1
NM_001318.4 start_lost

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0610
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1
Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 177 CDS bases. Genomic position: 63910174. Lost 0.457 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CSHL1NM_022579.3 linkc.285G>C p.Met95Ile missense_variant Exon 3 of 5 ENST00000309894.6 NP_072101.1 Q14406-1I6L999

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CSHL1ENST00000309894.6 linkc.285G>C p.Met95Ile missense_variant Exon 3 of 5 5 NM_022579.3 ENSP00000309524.5 Q14406-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
84
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.285G>C (p.M95I) alteration is located in exon 3 (coding exon 3) of the CSHL1 gene. This alteration results from a G to C substitution at nucleotide position 285, causing the methionine (M) at amino acid position 95 to be replaced by an isoleucine (I). 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
0.25
BayesDel_addAF
Benign
-0.070
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
9.1
DANN
Benign
0.84
DEOGEN2
Benign
0.21
.;.;.;.;.;.;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.26
N
LIST_S2
Uncertain
0.87
D;T;T;D;D;D;T
M_CAP
Benign
0.072
D
MetaRNN
Benign
0.14
T;T;T;T;T;T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
2.0
.;.;.;.;.;.;M
PrimateAI
Benign
0.40
T
PROVEAN
Benign
-1.8
N;N;.;N;N;N;N
REVEL
Benign
0.25
Sift
Uncertain
0.011
D;T;.;D;D;D;D
Sift4G
Uncertain
0.026
D;D;D;D;T;D;D
Polyphen
0.077, 0.065, 0.095
.;.;.;B;B;.;B
Vest4
0.14
MutPred
0.55
.;.;.;.;.;.;Loss of phosphorylation at T91 (P = 0.1587);
MVP
0.67
MPC
0.042
ClinPred
0.35
T
GERP RS
0.23
Varity_R
0.56
gMVP
0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-61987801; API