5-132294955-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_003059.3(SLC22A4):c.339C>T(p.Cys113=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00321 in 1,604,958 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0033 (11 hom.)
• Consequence: SLC22A4 NM_003059.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.377

Genes affected

SLC22A4 (HGNC:10968): (solute carrier family 22 member 4) Polyspecific organic cation transporters in the liver, kidney, intestine, and other organs are critical for elimination of many endogenous small organic cations as well as a wide array of drugs and environmental toxins. The encoded protein is an organic cation transporter and plasma integral membrane protein containing eleven putative transmembrane domains as well as a nucleotide-binding site motif. Transport by this protein is at least partially ATP-dependent. [provided by RefSeq, Jul 2008]

P4HA2 (HGNC:8547): (prolyl 4-hydroxylase subunit alpha 2) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 5-132294955-C-T is Benign according to our data. Variant chr5-132294955-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1669687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-132294955-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.377 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC22A4	NM_003059.3	c.339C>T	p.Cys113=	synonymous_variant	1/10	ENST00000200652.4
SLC22A4	XM_047417594.1	c.339C>T	p.Cys113=	synonymous_variant	1/8
SLC22A4	XM_011543589.3	c.339C>T	p.Cys113=	synonymous_variant	1/8
SLC22A4	XM_006714675.5	c.-86C>T		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC22A4	ENST00000200652.4	c.339C>T	p.Cys113=	synonymous_variant	1/10	1	NM_003059.3	P1
P4HA2	ENST00000471826.1	n.138+223G>A		intron_variant, non_coding_transcript_variant		1
P4HA2	ENST00000431054.5	c.78+223G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00574

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00200 AC: 457 AN: 228704 Hom.: 0 AF XY: 0.00192 AC XY: 240 AN XY: 125110

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.000394

Gnomad ASJ exome AF: 0.000522

Gnomad EAS exome AF: 0.0000589

Gnomad SAS exome AF: 0.000275

Gnomad FIN exome AF: 0.00468

Gnomad NFE exome AF: 0.00318

Gnomad OTH exome AF: 0.00194

GnomAD4 exome AF: 0.00332 AC: 4825 AN: 1452632 Hom.: 11 Cov.: 31 AF XY: 0.00313 AC XY: 2263 AN XY: 721892

Gnomad4 AFR exome AF: 0.000480

Gnomad4 AMR exome AF: 0.000367

Gnomad4 ASJ exome AF: 0.000424

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000329

Gnomad4 FIN exome AF: 0.00442

Gnomad4 NFE exome AF: 0.00397

Gnomad4 OTH exome AF: 0.00208

GnomAD4 genome AF: 0.00211 AC: 321 AN: 152326 Hom.: 0 Cov.: 32 AF XY: 0.00211 AC XY: 157 AN XY: 74492

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00574

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00236 Hom.: 0

Bravo AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 19, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	SLC22A4: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	13
Dann	Benign	0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs11568502; hg19: chr5-131630648; COSMIC: COSV99569251; COSMIC: COSV99569251;