rs666636

Positions:

• chr16-56567808-A-C
• chr16-56567808-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032935.3(MT4):​c.89A>C​(p.Tyr30Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,674 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y30C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MT4 NM_032935.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.02

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11172706).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MT4	NM_032935.3	c.89A>C	p.Tyr30Ser	missense_variant	2/3	ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.89A>C	p.Tyr30Ser	missense_variant	2/3	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+2867T>G		intron_variant				ENSP00000507981.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460674 Hom.: 0 Cov.: 36 AF XY: 0.00000413 AC XY: 3 AN XY: 726656

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.78
DEOGEN2	Benign	0.057	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.1	T
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.20
Sift	Benign	0.064	T
Sift4G	Benign	0.22	T
Polyphen		0.0	B
Vest4		0.29
MutPred		0.40		Gain of loop (P = 0.0097);
MVP		0.030
MPC		0.020
ClinPred		0.82	D
GERP RS		5.7
Varity_R		0.11
gMVP		0.36

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: rs666636; hg19: chr16-56601720;