Genetic Variant MFSD12:p.Gly395Ser (chr19-3546266-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_174983.5(MFSD12):c.1183G>A(p.Gly395Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00821 in 1,610,588 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.0047 ( 5 hom., cov: 33)

Exomes 𝑓: 0.0086 ( 81 hom. )

Consequence

MFSD12
NM_174983.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.27

Variant links:

Genes affected

MFSD12 (HGNC:28299): (major facilitator superfamily domain containing 12) Enables cysteine transmembrane transporter activity. Involved in cysteine transmembrane transport; pigment metabolic process involved in pigmentation; and regulation of melanin biosynthetic process. Located in lysosome and melanosome. Part of late endosome. [provided by Alliance of Genome Resources, Apr 2022]

MFSD12 links:

ENSG00000267436 (HGNC:56727): (MFSD12 antisense RNA 1)

ENSG00000267436 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015567243).

BP6

Variant 19-3546266-C-T is Benign according to our data. Variant chr19-3546266-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2648992.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD12	NM_174983.5 link	c.1183G>A	p.Gly395Ser	missense_variant	Exon 7 of 10	ENST00000355415.7	NP_778148.2	Q6NUT3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD12	ENST00000355415.7 link	c.1183G>A	p.Gly395Ser	missense_variant	Exon 7 of 10	1	NM_174983.5	ENSP00000347583.1		Q6NUT3-1

Frequencies

GnomAD3 genomes

AF:

0.00474

AC:

721

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00181

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00883

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00356

AC:

856

AN:

240426

Hom.:

AF XY:

0.00354

AC XY:

465

AN XY:

131376

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.00104

Gnomad ASJ exome

AF:

0.000919

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000994

Gnomad FIN exome

AF:

0.000690

Gnomad NFE exome

AF:

0.00691

Gnomad OTH exome

AF:

0.00428

GnomAD4 exome

AF:

0.00858

AC:

12505

AN:

1458274

Hom.:

Cov.:

AF XY:

0.00817

AC XY:

5925

AN XY:

725322

show subpopulations

Gnomad4 AFR exome

AF:

0.00126

Gnomad4 AMR exome

AF:

0.00127

Gnomad4 ASJ exome

AF:

0.00108

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.000105

Gnomad4 FIN exome

AF:

0.000578

Gnomad4 NFE exome

AF:

0.0107

Gnomad4 OTH exome

AF:

0.00670

GnomAD4 genome

AF:

0.00474

AC:

722

AN:

152314

Hom.:

Cov.:

AF XY:

0.00416

AC XY:

310

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00180

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000471

Gnomad4 NFE

AF:

0.00885

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00573

Hom.:

Bravo

AF:

0.00459

TwinsUK

AF:

0.00890

AC:

ALSPAC

AF:

0.00856

AC:

ESP6500AA

AF:

0.00140

AC:

ESP6500EA

AF:

0.00684

AC:

ExAC

AF:

0.00331

AC:

400

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Apr 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MFSD12: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.060

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

.;D;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.016

T;T;T;T

MetaSVM

Uncertain

0.52

MutationAssessor

Benign

2.0

.;M;.;.

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-4.9

.;D;.;.

REVEL

Uncertain

0.60

Sift

Benign

0.050

.;D;.;.

Sift4G

Uncertain

0.029

D;T;T;D

Polyphen

0.99, 1.0

.;D;D;.

Vest4

0.61, 0.64

MVP

0.74

ClinPred

0.026

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.59

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over