chr22-46308713-G-T

Position:

• chr22-46308713-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016426.7(GTSE1):​c.532G>T​(p.Val178Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00266 in 1,613,696 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V178M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.014 (46 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (45 hom.)
• Consequence: GTSE1 NM_016426.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.35

Genes affected

GTSE1 (HGNC:13698): (G2 and S-phase expressed 1) The protein encoded by this gene is only expressed in the S and G2 phases of the cell cycle, where it colocalizes with cytoplasmic tubulin and microtubules. In response to DNA damage, the encoded protein accumulates in the nucleus and binds the tumor suppressor protein p53, shuttling it out of the nucleus and repressing its ability to induce apoptosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022632778).
• BP6: Variant 22-46308713-G-T is Benign according to our data. Variant chr22-46308713-G-T is described in ClinVar as [Benign]. Clinvar id is 777737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0144 (2201/152384) while in subpopulation AFR AF= 0.0498 (2072/41594). AF 95% confidence interval is 0.048. There are 46 homozygotes in gnomad4. There are 1084 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 46 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GTSE1	NM_016426.7	c.532G>T	p.Val178Leu	missense_variant	4/12	ENST00000454366.2
GTSE1	XM_047441391.1	c.532G>T	p.Val178Leu	missense_variant	3/11
GTSE1	XM_047441392.1	c.532G>T	p.Val178Leu	missense_variant	4/10
GTSE1	XR_007067974.1	n.615G>T		non_coding_transcript_exon_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GTSE1	ENST00000454366.2	c.532G>T	p.Val178Leu	missense_variant	4/12	1	NM_016426.7	P1

Frequencies

GnomAD3 genomes AF: 0.0144 AC: 2194 AN: 152266 Hom.: 46 Cov.: 33

Gnomad AFR AF: 0.0498

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00615

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00372 AC: 925 AN: 248786 Hom.: 20 AF XY: 0.00289 AC XY: 390 AN XY: 135066

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.00206

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000206

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00143 AC: 2089 AN: 1461312 Hom.: 45 Cov.: 33 AF XY: 0.00125 AC XY: 907 AN XY: 726924

Gnomad4 AFR exome AF: 0.0493

Gnomad4 AMR exome AF: 0.00273

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000638

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0144 AC: 2201 AN: 152384 Hom.: 46 Cov.: 33 AF XY: 0.0145 AC XY: 1084 AN XY: 74528

Gnomad4 AFR AF: 0.0498

Gnomad4 AMR AF: 0.00614

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.000785 Hom.: 3

Bravo AF: 0.0164

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0433 AC: 190

ESP6500EA AF: 0.000234 AC: 2

ExAC AF: 0.00456 AC: 553

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0090
DANN	Benign	0.35
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0049	N
MetaRNN	Benign	0.0023	T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.0030
Sift	Benign	0.84	T
Sift4G	Benign	0.91	T
Vest4		0.028
MVP		0.014
MPC		0.14
ClinPred		0.0025	T
GERP RS		-8.9
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs35141277; hg19: chr22-46704610; COSMIC: COSV99069738;