chr11-2304154-G-A

Position:

• chr11-2304154-G-A

Variant summary

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

The NM_139022.3(TSPAN32):​c.229G>A​(p.Val77Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,590,056 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (12 hom.)
• Consequence: TSPAN32 NM_139022.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.493

Genes affected

TSPAN32 (HGNC:13410): (tetraspanin 32) This gene, which is a member of the tetraspanin superfamily, is one of several tumor-suppressing subtransferable fragments located in the imprinted gene domain of chromosome 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocortical carcinoma, and lung, ovarian and breast cancers. This gene is located among several imprinted genes; however, this gene, as well as the tumor-suppressing subchromosomal transferable fragment 4, escapes imprinting. This gene may play a role in malignancies and diseases that involve this region, and it is also involved in hematopoietic cell function. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005427748).
• BP6: Variant 11-2304154-G-A is Benign according to our data. Variant chr11-2304154-G-A is described in ClinVar as [Benign]. Clinvar id is 734465.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 = 0.0065 (990/152234) while in subpopulation AFR AF= 0.0223 (927/41544). AF 95% confidence interval is 0.0211. There are 13 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSPAN32	NM_139022.3	c.229G>A	p.Val77Met	missense_variant	3/10	ENST00000182290.9	NP_620591.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSPAN32	ENST00000182290.9	c.229G>A	p.Val77Met	missense_variant	3/10	1	NM_139022.3	ENSP00000182290	P2

Frequencies

GnomAD3 genomes AF: 0.00648 AC: 985 AN: 152116 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00180 AC: 381 AN: 211670 Hom.: 4 AF XY: 0.00142 AC XY: 162 AN XY: 113874

Gnomad AFR exome AF: 0.0250

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.000108

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000755

Gnomad OTH exome AF: 0.00168

GnomAD4 exome AF: 0.000720 AC: 1035 AN: 1437822 Hom.: 12 Cov.: 31 AF XY: 0.000627 AC XY: 447 AN XY: 712860

Gnomad4 AFR exome AF: 0.0237

Gnomad4 AMR exome AF: 0.00158

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000291

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000527

Gnomad4 OTH exome AF: 0.00150

GnomAD4 genome AF: 0.00650 AC: 990 AN: 152234 Hom.: 13 Cov.: 32 AF XY: 0.00609 AC XY: 453 AN XY: 74436

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.00287

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00142 Hom.: 2

Bravo AF: 0.00741

ESP6500AA AF: 0.0200 AC: 88

ESP6500EA AF: 0.000466 AC: 4

ExAC AF: 0.00186 AC: 224

Asia WGS AF: 0.00173 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 20, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.11	T;T;.;.;T
Eigen	Benign	-0.96
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.64	T;T;T;T;.
MetaRNN	Benign	0.0054	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.34	N;.;N;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.27	N;.;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.28	T;.;T;T;T
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.84	P;P;P;.;P
Vest4		0.10
MVP		0.32
MPC		0.058
ClinPred		0.018	T
GERP RS		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.045
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2234296; hg19: chr11-2325384;