rs396230

Positions:

• chr16-56568704-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000219162.4(MT4):​c.98-137T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.193 in 581,374 control chromosomes in the GnomAD database, including 11,929 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3838 hom., cov: 30)
  • Exomes 𝑓: 0.19 (8091 hom.)
• Consequence: MT4 ENST00000219162.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.403

Genes affected

MT4 (HGNC:18705): (metallothionein 4) Predicted to enable metal ion binding activity. Predicted to be involved in cellular response to metal ion; cellular zinc ion homeostasis; and detoxification of copper ion. Predicted to act upstream of or within cellular metal ion homeostasis. Predicted to be active in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

BBS2 (HGNC:967): (Bardet-Biedl syndrome 2) This gene is a member of the Bardet-Biedl syndrome (BBS) gene family. Bardet-Biedl syndrome is an autosomal recessive disorder characterized by severe pigmentary retinopathy, obesity, polydactyly, renal malformation and cognitive disability. The proteins encoded by BBS gene family members are structurally diverse and the similar phenotypes exhibited by mutations in BBS gene family members is likely due to their shared roles in cilia formation and function. Many BBS proteins localize to the basal bodies, ciliary axonemes, and pericentriolar regions of cells. BBS proteins may also be involved in intracellular trafficking via microtubule-related transport. The protein encoded by this gene forms a multiprotein BBSome complex with seven other BBS proteins.[provided by RefSeq, Oct 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MT4	NM_032935.3	c.98-137T>C		intron_variant		ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.98-137T>C		intron_variant		1	NM_032935.3	ENSP00000219162	P1
BBS2	ENST00000682930.1	c.42+1971A>G		intron_variant				ENSP00000507981

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32235 AN: 151876 Hom.: 3839 Cov.: 30

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0938

Gnomad EAS AF: 0.265

Gnomad SAS AF: 0.238

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.191

GnomAD4 exome AF: 0.187 AC: 80184 AN: 429378 Hom.: 8091 AF XY: 0.188 AC XY: 42467 AN XY: 226296

Gnomad4 AFR exome AF: 0.327

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.274

Gnomad4 SAS exome AF: 0.253

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.172

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.212 AC: 32279 AN: 151996 Hom.: 3838 Cov.: 30 AF XY: 0.213 AC XY: 15834 AN XY: 74284

Gnomad4 AFR AF: 0.323

Gnomad4 AMR AF: 0.175

Gnomad4 ASJ AF: 0.0938

Gnomad4 EAS AF: 0.265

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.169

Gnomad4 NFE AF: 0.163

Gnomad4 OTH AF: 0.193

Alfa AF: 0.174 Hom.: 2062

Bravo AF: 0.217

Asia WGS AF: 0.264 AC: 918 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	6.9
DANN	Benign	0.75

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: rs396230; hg19: chr16-56602616; COSMIC: COSV54642393;