13-113822006-C-T

Position:

• chr13-113822006-C-T

Variant summary

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

The ENST00000327773.7(GAS6):​c.1834G>A​(p.Glu612Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00252 in 1,556,086 control chromosomes in the GnomAD database, including 81 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.014 (45 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (36 hom.)
• Consequence: GAS6 ENST00000327773.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0770

Genes affected

GAS6 (HGNC:4168): (growth arrest specific 6) This gene encodes a gamma-carboxyglutamic acid (Gla)-containing protein thought to be involved in the stimulation of cell proliferation. This gene is frequently overexpressed in many cancers and has been implicated as an adverse prognostic marker. Elevated protein levels are additionally associated with a variety of disease states, including venous thromboembolic disease, systemic lupus erythematosus, chronic renal failure, and preeclampsia. [provided by RefSeq, Aug 2014]

GAS6-AS1 (HGNC:39826): (GAS6 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029712021).
• BP6: Variant 13-113822006-C-T is Benign according to our data. Variant chr13-113822006-C-T is described in ClinVar as [Benign]. Clinvar id is 786243.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 = 0.0136 (2073/152344) while in subpopulation AFR AF= 0.0461 (1915/41574). AF 95% confidence interval is 0.0443. There are 45 homozygotes in gnomad4. There are 959 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 45 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAS6	NM_000820.4	c.1834G>A	p.Glu612Lys	missense_variant	14/15	ENST00000327773.7	NP_000811.1
GAS6-AS1	NR_044995.2	n.82+6315C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAS6	ENST00000327773.7	c.1834G>A	p.Glu612Lys	missense_variant	14/15	1	NM_000820.4	ENSP00000331831	P1
GAS6-AS1	ENST00000458001.2	n.62+6315C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2072 AN: 152226 Hom.: 45 Cov.: 34

Gnomad AFR AF: 0.0462

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

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: 0.000191

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00330 AC: 527 AN: 159730 Hom.: 10 AF XY: 0.00253 AC XY: 218 AN XY: 86020

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00259

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000430

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00132 AC: 1848 AN: 1403742 Hom.: 36 Cov.: 32 AF XY: 0.00111 AC XY: 768 AN XY: 693320

Gnomad4 AFR exome AF: 0.0460

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.000113

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00312

GnomAD4 genome AF: 0.0136 AC: 2073 AN: 152344 Hom.: 45 Cov.: 34 AF XY: 0.0129 AC XY: 959 AN XY: 74492

Gnomad4 AFR AF: 0.0461

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.000521 Hom.: 2

Bravo AF: 0.0162

ESP6500AA AF: 0.0460 AC: 197

ESP6500EA AF: 0.000353 AC: 3

ExAC AF: 0.00301 AC: 348

Asia WGS AF: 0.00144 AC: 6 AN: 3478

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	Apr 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	7.4
DANN	Benign	0.93
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.17
Sift	Benign	0.36	T
Sift4G	Benign	0.24	T
Vest4		0.14
MVP		0.82
MPC		0.27
ClinPred		0.0046	T
GERP RS		1.2
Varity_R		0.037
gMVP		0.69

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: rs73583241; hg19: chr13-114524979;