4-682080-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032219.4(SLC49A3):​c.1558G>T​(p.Gly520Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000016 in 1,252,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 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. G520R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: SLC49A3 NM_032219.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10001704).

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>T	p.Gly520Cys	missense	Exon 10 of 10	NP_115595.2
	SLC49A3	NM_001294341.2		c.1561G>T	p.Gly521Cys	missense	Exon 10 of 10	NP_001281270.1	Q6UXD7-1
	SLC49A3	NM_001378061.1		c.1324G>T	p.Gly442Cys	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>T	p.Gly520Cys	missense	Exon 10 of 10	ENSP00000320234.4	Q6UXD7-2
	SLC49A3	ENST00000404286.6	TSL:1	c.1561G>T	p.Gly521Cys	missense	Exon 10 of 10	ENSP00000384616.2	Q6UXD7-1
	SLC49A3	ENST00000894937.1		c.1441G>T	p.Gly481Cys	missense	Exon 9 of 9	ENSP00000564996.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000160 AC: 2 AN: 1252960 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 611090

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 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: 0.00 AC: 0 AN: 31232

South Asian (SAS) AF: 0.0000174 AC: 1 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: 9.99e-7 AC: 1 AN: 1000528

Other (OTH) AF: 0.00 AC: 0 AN: 50022

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.10	T
MetaSVM	Uncertain	0.018	D
PhyloP100		-0.31
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.17	N
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D
Polyphen		0.92	P
Vest4		0.18
MutPred		0.16		Loss of catalytic residue at P517 (P = 0.0775)
MVP		0.38
MPC		0.19
ClinPred		0.15	T
GERP RS		-2.9
Varity_R		0.13
gMVP		0.11
Mutation Taster		=96/4	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;