10-116940557-G-T

Position:

• chr10-116940557-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001127211.3(SHTN1):​c.767C>A​(p.Ser256Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000212 in 1,461,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: not found (cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SHTN1 NM_001127211.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08180386).
• BS2: High AC in GnomAdExome4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHTN1	NM_001127211.3	c.767C>A	p.Ser256Tyr	missense_variant	9/17	ENST00000355371.9	NP_001120683.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHTN1	ENST00000355371.9	c.767C>A	p.Ser256Tyr	missense_variant	9/17	2	NM_001127211.3	ENSP00000347532.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461502 Hom.: 0 Cov.: 31 AF XY: 0.0000206 AC XY: 15 AN XY: 727038

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2024

The c.767C>A (p.S256Y) alteration is located in exon 9 (coding exon 9) of the SHTN1 gene. This alteration results from a C to A substitution at nucleotide position 767, causing the serine (S) at amino acid position 256 to be replaced by a tyrosine (Y). 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	0.18
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Benign	0.92
DEOGEN2	Benign	0.058	.;.;T;.;.
Eigen	Benign	-0.019
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.52	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.082	T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;.;L;L;.
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.0	.;.;N;N;N
REVEL	Benign	0.058
Sift	Benign	0.067	.;.;T;T;T
Sift4G	Benign	0.52	T;T;T;T;T
Polyphen		0.44	B;.;B;.;.
Vest4		0.40
MutPred		0.20		Loss of phosphorylation at S256 (P = 0.0418);.;Loss of phosphorylation at S256 (P = 0.0418);Loss of phosphorylation at S256 (P = 0.0418);.;
MVP		0.043
MPC		0.77
ClinPred		0.21	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.059
gMVP		0.32

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: rs767881410; hg19: chr10-118700068;