Genetic Variant NM_001127211.3:c.1618C>T (chr10-116901820-G-A) – 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_001127211.3(SHTN1):c.1618C>T(p.Pro540Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,448,576 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P540A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

SHTN1
NM_001127211.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.43

Publications

0 publications found

Variant links:

Genes affected

SHTN1 (HGNC:29319): (shootin 1) Enables identical protein binding activity. Involved in positive regulation of neuron migration. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SHTN1 links:

ENO4 (HGNC:31670): (enolase 4) Predicted to enable phosphopyruvate hydratase activity. Predicted to be involved in glycolytic process and regulation of vacuole fusion, non-autophagic. Predicted to act upstream of or within cilium organization and flagellated sperm motility. Predicted to be located in sperm principal piece. Predicted to be part of phosphopyruvate hydratase complex. [provided by Alliance of Genome Resources, Apr 2022]

ENO4 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=0.038508058).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127211.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHTN1	NM_001127211.3	MANE Select	c.1618C>T	p.Pro540Ser	missense	Exon 16 of 17	NP_001120683.1	A0MZ66-1
SHTN1	NM_001258298.2		c.1438C>T	p.Pro480Ser	missense	Exon 15 of 16	NP_001245227.1	A0MZ66-5
SHTN1	NM_001258299.2		c.1618C>T	p.Pro540Ser	missense	Exon 16 of 17	NP_001245228.1	A0MZ66-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SHTN1	ENST00000355371.9	TSL:2 MANE Select	c.1618C>T	p.Pro540Ser	missense	Exon 16 of 17	ENSP00000347532.4	A0MZ66-1
SHTN1	ENST00000392903.3	TSL:1	c.1618C>T	p.Pro540Ser	missense	Exon 16 of 17	ENSP00000376636.3	A0MZ66-4
SHTN1	ENST00000615301.4	TSL:1	c.1359+9970C>T		intron	N/A	ENSP00000480109.1	A0MZ66-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1448576

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720624

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32304

American (AMR)

AF:

0.00

AC:

AN:

40338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25664

East Asian (EAS)

AF:

0.00

AC:

AN:

39264

South Asian (SAS)

AF:

0.0000119

AC:

AN:

83726

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108472

Other (OTH)

AF:

0.00

AC:

AN:

59802

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.0028

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.41

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.74

M_CAP

Benign

0.0013

MetaRNN

Benign

0.039

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

1.4

PrimateAI

Benign

0.37

PROVEAN

Benign

0.080

REVEL

Benign

0.079

Sift

Benign

0.14

Sift4G

Benign

0.22

Polyphen

0.013

Vest4

0.11

MutPred

0.15

Gain of phosphorylation at P540 (P = 0.0112)

MVP

0.043

MPC

0.44

ClinPred

0.049

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.030

gMVP

0.27

Mutation Taster

=92/8

polymorphism

(source)

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