chr12-53253667-G-A

Position:

• chr12-53253667-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The ENST00000329548.5(MFSD5):​c.832G>A​(p.Gly278Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000457 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: MFSD5 ENST00000329548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.08

Genes affected

MFSD5 (HGNC:28156): (major facilitator superfamily domain containing 5) Predicted to enable molybdate ion transmembrane transporter activity. Predicted to be involved in molybdate ion transport. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29717556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD5	NM_032889.5	c.832G>A	p.Gly278Arg	missense_variant	2/2	ENST00000329548.5	NP_116278.3
MFSD5	NM_001170790.2	c.1153G>A	p.Gly385Arg	missense_variant	2/2		NP_001164261.1
MFSD5	XM_005269197.2	c.1153G>A	p.Gly385Arg	missense_variant	3/3		XP_005269254.1
MFSD5	XM_005269198.5	c.832G>A	p.Gly278Arg	missense_variant	2/2		XP_005269255.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFSD5	ENST00000329548.5	c.832G>A	p.Gly278Arg	missense_variant	2/2	1	NM_032889.5	ENSP00000332624.5
MFSD5	ENST00000534842.1	c.1153G>A	p.Gly385Arg	missense_variant	2/2	2		ENSP00000442688.1
MFSD5	ENST00000551660.2	c.1153G>A	p.Gly385Arg	missense_variant	2/2	2		ENSP00000449354.2

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000211 AC: 53 AN: 251306 Hom.: 0 AF XY: 0.000155 AC XY: 21 AN XY: 135860

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000486 AC: 711 AN: 1461684 Hom.: 0 Cov.: 33 AF XY: 0.000455 AC XY: 331 AN XY: 727168

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000615

Gnomad4 OTH exome AF: 0.000215

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152184 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74348

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000350 Hom.: 0

Bravo AF: 0.000162

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000157 AC: 19

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.1153G>A (p.G385R) alteration is located in exon 2 (coding exon 2) of the MFSD5 gene. This alteration results from a G to A substitution at nucleotide position 1153, causing the glycine (G) at amino acid position 385 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.071	.;T;T
Eigen	Benign	0.096
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.30	T;T;T
MetaSVM	Uncertain	0.082	D
MutationAssessor	Uncertain	2.3	.;.;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.4	N;N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.018	D;D;D
Sift4G	Benign	0.25	T;T;T
Polyphen		0.99	.;.;D
Vest4		0.27
MutPred		0.54		.;.;Gain of solvent accessibility (P = 6e-04);
MVP		0.78
MPC		0.51
ClinPred		0.13	T
GERP RS		4.2
Varity_R		0.17
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs142428878; hg19: chr12-53647451;