rs669293

Variant names:

• chr16-56568440-T-C
• rs669293
• NM_032935.3:c.98-401T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032935.3(MT4):​c.98-401T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 151,742 control chromosomes in the GnomAD database, including 3,831 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 (3831 hom., cov: 29)
• Consequence: MT4 NM_032935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.01
• Publications: 3 publications found

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]

BBS2 Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Myriad Women’s Health
• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• retinitis pigmentosa 74

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Bardet-Biedl syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• 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 rank	MANE	Protein	UniProt
MT4	NM_032935.3	c.98-401T>C		intron_variant	Intron 2 of 2	ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.98-401T>C		intron_variant	Intron 2 of 2	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+2235A>G		intron_variant	Intron 2 of 18			ENSP00000507981.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32174 AN: 151624 Hom.: 3832 Cov.: 29

Gnomad AFR AF: 0.323

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.175

Gnomad ASJ AF: 0.0939

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

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.212 AC: 32218 AN: 151742 Hom.: 3831 Cov.: 29 AF XY: 0.213 AC XY: 15796 AN XY: 74142

African (AFR) AF: 0.323 AC: 13352 AN: 41312

American (AMR) AF: 0.175 AC: 2669 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.0939 AC: 325 AN: 3462

East Asian (EAS) AF: 0.265 AC: 1356 AN: 5112

South Asian (SAS) AF: 0.236 AC: 1132 AN: 4804

European-Finnish (FIN) AF: 0.169 AC: 1784 AN: 10576

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11083 AN: 67906

Other (OTH) AF: 0.193 AC: 409 AN: 2114

Alfa AF: 0.211 Hom.: 702

Bravo AF: 0.217

Asia WGS AF: 0.263 AC: 912 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.052
DANN	Benign	0.50
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs669293; hg19: chr16-56602352;