17-63910486-C-A

Variant names:

• chr17-63910486-C-A
• rs200860141
• NM_022579.3:c.240G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022579.3(CSHL1):​c.240G>T​(p.Gln80His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CSHL1 NM_022579.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 1 publications found

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]

ENSG00000303015 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSHL1	NM_022579.3	MANE Select	c.240G>T	p.Gln80His	missense	Exon 3 of 5	NP_072101.1	Q14406-1
	CSHL1	NM_001321069.2		c.123G>T	p.Gln41His	missense	Exon 3 of 5	NP_001307998.1
	CSHL1	NM_001321067.2		c.60G>T	p.Gln20His	missense	Exon 2 of 4	NP_001307996.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CSHL1	ENST00000309894.6	TSL:5 MANE Select	c.240G>T	p.Gln80His	missense	Exon 3 of 5	ENSP00000309524.5	Q14406-1
	CSHL1	ENST00000346606.10	TSL:1	c.-43G>T		5_prime_UTR	Exon 2 of 4	ENSP00000316360.10	Q14406-4
	CSHL1	ENST00000259003.14	TSL:1	c.74-20G>T		intron	N/A	ENSP00000259003.10	A0A0B4J1R0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251490 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461888 Hom.: 0 Cov.: 83 AF XY: 0.00 AC XY: 0 AN XY: 727244

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.44	T
MetaSVM	Uncertain	-0.063	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.028	D
Sift4G	Uncertain	0.011	D
Polyphen		0.81	P
Vest4		0.41
MutPred		0.42		Loss of disorder (P = 0.1683)
MVP		0.91
MPC		0.18
ClinPred		0.76	D
GERP RS		2.4
Varity_R		0.24
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.26		Position offset: -20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs200860141; hg19: chr17-61987846;