rs762604

Variant names:

• chr16-56568759-C-T
• rs762604
• NM_032935.3:c.98-82C>T

Variant summary

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

The NM_032935.3(MT4):​c.98-82C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 959,410 control chromosomes in the GnomAD database, including 38,108 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 (4470 hom., cov: 31)
  • Exomes 𝑓: 0.28 (33638 hom.)
• Consequence: MT4 NM_032935.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.120
• Publications: 5 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=-0.7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT4	NM_032935.3	c.98-82C>T		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.98-82C>T		intron_variant	Intron 2 of 2	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+1916G>A		intron_variant	Intron 2 of 18			ENSP00000507981.1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32301 AN: 152014 Hom.: 4469 Cov.: 31

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.344

Gnomad AMR AF: 0.200

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.0520

Gnomad SAS AF: 0.127

Gnomad FIN AF: 0.337

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.230

GnomAD4 exome AF: 0.276 AC: 223074 AN: 807278 Hom.: 33638 AF XY: 0.273 AC XY: 111791 AN XY: 409590

African (AFR) AF: 0.0476 AC: 902 AN: 18966

American (AMR) AF: 0.152 AC: 3717 AN: 24394

Ashkenazi Jewish (ASJ) AF: 0.253 AC: 3796 AN: 15000

East Asian (EAS) AF: 0.0722 AC: 2347 AN: 32514

South Asian (SAS) AF: 0.122 AC: 5628 AN: 46048

European-Finnish (FIN) AF: 0.331 AC: 15376 AN: 46508

Middle Eastern (MID) AF: 0.184 AC: 733 AN: 3974

European-Non Finnish (NFE) AF: 0.311 AC: 181377 AN: 583044

Other (OTH) AF: 0.250 AC: 9198 AN: 36830

GnomAD4 genome AF: 0.212 AC: 32292 AN: 152132 Hom.: 4470 Cov.: 31 AF XY: 0.209 AC XY: 15578 AN XY: 74372

African (AFR) AF: 0.0529 AC: 2196 AN: 41538

American (AMR) AF: 0.199 AC: 3048 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 858 AN: 3470

East Asian (EAS) AF: 0.0517 AC: 267 AN: 5162

South Asian (SAS) AF: 0.128 AC: 615 AN: 4820

European-Finnish (FIN) AF: 0.337 AC: 3560 AN: 10572

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20890 AN: 67972

Other (OTH) AF: 0.228 AC: 481 AN: 2106

Alfa AF: 0.260 Hom.: 9215

Bravo AF: 0.196

Asia WGS AF: 0.0890 AC: 314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs762604; hg19: chr16-56602671; COSMIC: COSV54642402;