chr4-25662705-CA-C

Variant names:

• chr4-25662705-CA-C
• NM_006424.3:c.114delA

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001177998.2(SLC34A2):​c.113-2delA variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SLC34A2 NM_001177998.2 splice_acceptor, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.78
• Publications: 4 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: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06521739 fraction of the gene. Cryptic splice site detected, with MaxEntScore 9.8, offset of -2, new splice context is: accccttttgcttgtttcAGcga. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-25662705-CA-C is Pathogenic according to our data. Variant chr4-25662705-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 5715.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001177998.2. 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.114delA	p.Asp39IlefsTer7	frameshift splice_region	Exon 3 of 13	NP_006415.3	O95436-1
	SLC34A2	NM_001177998.2		c.113-2delA		splice_acceptor intron	N/A	NP_001171469.2	O95436-2
	SLC34A2	NM_001177999.2		c.113-2delA		splice_acceptor intron	N/A	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.114delA	p.Asp39IlefsTer7	frameshift splice_region	Exon 3 of 13	ENSP00000371483.3	O95436-1
	SLC34A2	ENST00000503434.5	TSL:1	c.113-2delA		splice_acceptor intron	N/A	ENSP00000423021.1	O95436-2
	SLC34A2	ENST00000504570.5	TSL:1	c.113-2delA		splice_acceptor intron	N/A	ENSP00000425501.1	O95436-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	PULMONARY ALVEOLAR MICROLITHIASIS (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.8
Mutation Taster		=16/184	disease causing (fs/PTC)

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

hg19: chr4-25664327;