rs11643815

Variant names:

• chr16-56568886-G-A
• rs11643815
• NM_032935.3:c.143G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-56568886-G-A
• chr16-56568886-G-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.143G>A​(p.Gly48Asp) variant causes a missense change. The variant allele was found at a frequency of 0.124 in 1,606,480 control chromosomes in the GnomAD database, including 13,519 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.098 (919 hom., cov: 32)
  • Exomes 𝑓: 0.13 (12600 hom.)
• Consequence: MT4 NM_032935.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.09

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

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.003320247).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MT4	NM_032935.3	c.143G>A	p.Gly48Asp	missense_variant	Exon 3 of 3	ENST00000219162.4	NP_116324.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MT4	ENST00000219162.4	c.143G>A	p.Gly48Asp	missense_variant	Exon 3 of 3	1	NM_032935.3	ENSP00000219162.3
BBS2	ENST00000682930.1	c.42+1789C>T		intron_variant	Intron 2 of 18			ENSP00000507981.1

Frequencies

GnomAD3 genomes AF: 0.0979 AC: 14885 AN: 152102 Hom.: 919 Cov.: 32

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.250

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.144

Gnomad EAS AF: 0.00598

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.0967

GnomAD2 exomes AF: 0.108 AC: 26310 AN: 244600 AF XY: 0.109

Gnomad AFR exome AF: 0.0270

Gnomad AMR exome AF: 0.122

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.00576

Gnomad FIN exome AF: 0.103

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.127 AC: 184656 AN: 1454260 Hom.: 12600 Cov.: 31 AF XY: 0.126 AC XY: 91445 AN XY: 723354

Gnomad4 AFR exome AF: 0.0237 AC: 788 AN: 33310

Gnomad4 AMR exome AF: 0.120 AC: 5246 AN: 43864

Gnomad4 ASJ exome AF: 0.135 AC: 3477 AN: 25794

Gnomad4 EAS exome AF: 0.00244 AC: 96 AN: 39420

Gnomad4 SAS exome AF: 0.0981 AC: 8355 AN: 85126

Gnomad4 FIN exome AF: 0.103 AC: 5500 AN: 53224

Gnomad4 NFE exome AF: 0.139 AC: 153921 AN: 1107734

Gnomad4 Remaining exome AF: 0.111 AC: 6688 AN: 60056

GnomAD4 genome AF: 0.0978 AC: 14881 AN: 152220 Hom.: 919 Cov.: 32 AF XY: 0.0950 AC XY: 7071 AN XY: 74430

Gnomad4 AFR AF: 0.0289 AC: 0.0289133 AN: 0.0289133

Gnomad4 AMR AF: 0.100 AC: 0.10017 AN: 0.10017

Gnomad4 ASJ AF: 0.144 AC: 0.144297 AN: 0.144297

Gnomad4 EAS AF: 0.00599 AC: 0.00598918 AN: 0.00598918

Gnomad4 SAS AF: 0.0929 AC: 0.092869 AN: 0.092869

Gnomad4 FIN AF: 0.100 AC: 0.0999811 AN: 0.0999811

Gnomad4 NFE AF: 0.142 AC: 0.141876 AN: 0.141876

Gnomad4 OTH AF: 0.0952 AC: 0.0951705 AN: 0.0951705

Alfa AF: 0.116 Hom.: 2884

Bravo AF: 0.0932

TwinsUK AF: 0.146 AC: 541

ALSPAC AF: 0.137 AC: 528

ESP6500AA AF: 0.0292 AC: 128

ESP6500EA AF: 0.132 AC: 1135

ExAC AF: 0.109 AC: 13240

Asia WGS AF: 0.0600 AC: 208 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.45
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.3	T
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.33
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.32
MPC		0.16
ClinPred		0.024	T
GERP RS		5.9
Varity_R		0.69
gMVP		0.28
Mutation Taster		=35/65	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

Publications

LitVar

Other links and lift over

dbSNP: rs11643815; hg19: chr16-56602798; COSMIC: COSV54643125;