chr4-682080-C-G

Variant names:

• chr4-682080-C-G
• rs770490496
• NM_032219.4:c.1558G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032219.4(SLC49A3):​c.1558G>C​(p.Gly520Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 1,405,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: SLC49A3 NM_032219.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.312
• Publications: 0 publications found

Genes affected

SLC49A3 (HGNC:26177): (solute carrier family 49 member 3) Predicted to enable transmembrane transporter activity. Predicted to be involved in transmembrane transport. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

MYL5 (HGNC:7586): (myosin light chain 5) This gene encodes one of the myosin light chains, a component of the hexameric ATPase cellular motor protein myosin. Myosin is composed of two heavy chains, two nonphosphorylatable alkali light chains, and two phosphorylatable regulatory light chains. This gene product, one of the regulatory light chains, is expressed in fetal muscle and in adult retina, cerebellum, and basal ganglia. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.037323654).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032219.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC49A3	NM_032219.4	MANE Select	c.1558G>C	p.Gly520Arg	missense	Exon 10 of 10	NP_115595.2
	SLC49A3	NM_001294341.2		c.1561G>C	p.Gly521Arg	missense	Exon 10 of 10	NP_001281270.1	Q6UXD7-1
	SLC49A3	NM_001378061.1		c.1324G>C	p.Gly442Arg	missense	Exon 9 of 9	NP_001364990.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC49A3	ENST00000322224.9	TSL:1 MANE Select	c.1558G>C	p.Gly520Arg	missense	Exon 10 of 10	ENSP00000320234.4	Q6UXD7-2
	SLC49A3	ENST00000404286.6	TSL:1	c.1561G>C	p.Gly521Arg	missense	Exon 10 of 10	ENSP00000384616.2	Q6UXD7-1
	SLC49A3	ENST00000894937.1		c.1441G>C	p.Gly481Arg	missense	Exon 9 of 9	ENSP00000564996.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00000903 AC: 1 AN: 110718 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.0000144 AC: 18 AN: 1252960 Hom.: 0 Cov.: 31 AF XY: 0.00000982 AC XY: 6 AN XY: 611090

African (AFR) AF: 0.0000391 AC: 1 AN: 25596

American (AMR) AF: 0.00 AC: 0 AN: 20946

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17342

East Asian (EAS) AF: 0.0000320 AC: 1 AN: 31232

South Asian (SAS) AF: 0.00 AC: 0 AN: 57382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1000528

Other (OTH) AF: 0.000320 AC: 16 AN: 50022

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74486

African (AFR) AF: 0.0000481 AC: 2 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000338 AC: 4

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	8.9
DANN	Benign	0.92
DEOGEN2	Benign	0.020	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.29	T
PhyloP100		-0.31
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Polyphen		0.0090	B
Vest4		0.14
MutPred		0.12		Gain of MoRF binding (P = 0.0105)
MVP		0.32
MPC		0.085
ClinPred		0.013	T
GERP RS		-2.9
Varity_R		0.069
gMVP		0.072
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs770490496; hg19: chr4-675869;