4-25664267-G-A

Variant names:

• chr4-25664267-G-A
• rs137853142
• NM_006424.3:c.316G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP3_Strong

The NM_006424.3(SLC34A2):​c.316G>A​(p.Gly106Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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 pathogenic in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SLC34A2 NM_006424.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.76
• Publications: 11 publications found

Genes affected

SLC34A2 (HGNC:11020): (solute carrier family 34 member 2) The protein encoded by this gene is a pH-sensitive sodium-dependent phosphate transporter. Phosphate uptake is increased at lower pH. Defects in this gene are a cause of pulmonary alveolar microlithiasis. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, May 2010]

SLC34A2 Gene-Disease associations (from GenCC):

• pulmonary alveolar microlithiasis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_006424.3 (SLC34A2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006424.3. 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
	SLC34A2	NM_006424.3	MANE Select	c.316G>A	p.Gly106Arg	missense	Exon 4 of 13	NP_006415.3	O95436-1
	SLC34A2	NM_001177998.2		c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	NP_001171469.2	O95436-2
	SLC34A2	NM_001177999.2		c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	NP_001171470.2	O95436-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC34A2	ENST00000382051.8	TSL:1 MANE Select	c.316G>A	p.Gly106Arg	missense	Exon 4 of 13	ENSP00000371483.3	O95436-1
	SLC34A2	ENST00000503434.5	TSL:1	c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	ENSP00000423021.1	O95436-2
	SLC34A2	ENST00000504570.5	TSL:1	c.313G>A	p.Gly105Arg	missense	Exon 4 of 13	ENSP00000425501.1	O95436-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251480 AF XY: 0.0000147

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461618 Hom.: 0 Cov.: 34 AF XY: 0.0000220 AC XY: 16 AN XY: 727150

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000189 AC: 21 AN: 1111772

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000602 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.8
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.034	D
Polyphen		1.0	D
Vest4		0.94
MutPred		0.94		Gain of MoRF binding (P = 0.0333)
MVP		0.89
MPC		0.86
ClinPred		0.97	D
GERP RS		5.6
Varity_R		0.73
gMVP		0.94
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853142; hg19: chr4-25665889; COSMIC: COSV65942208; COSMIC: COSV65942208;