NM_022579.3:c.385A>C

Variant names:

• chr17-63910248-T-G
• rs61762514
• NM_022579.3:c.385A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022579.3(CSHL1):​c.385A>C​(p.Thr129Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CSHL1 NM_022579.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37030292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CSHL1	NM_022579.3	c.385A>C	p.Thr129Pro	missense_variant	Exon 4 of 5	ENST00000309894.6	NP_072101.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CSHL1	ENST00000309894.6	c.385A>C	p.Thr129Pro	missense_variant	Exon 4 of 5	5	NM_022579.3	ENSP00000309524.5

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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

GnomAD4 exome Cov.: 84

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74276

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	9.5
DANN	Benign	0.76
DEOGEN2	Benign	0.28	.;.;.;.;.;.;T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.70	T;T;T;T;T;T;T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.37	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.0030	D
MutationAssessor	Benign	1.8	.;.;.;.;.;.;L
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.6	D;N;.;N;N;D;N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D;D;.;D;D;D;D
Sift4G	Uncertain	0.026	D;T;T;T;T;D;T
Polyphen		0.68, 0.37, 0.73	.;.;.;P;B;.;P
Vest4		0.39
MutPred		0.53		.;.;.;.;.;.;Loss of helix (P = 0.0626);
MVP		0.48
MPC		0.050
ClinPred		0.47	T
GERP RS		0.76
Varity_R		0.42
gMVP		0.64

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: rs61762514; hg19: chr17-61987608;