1-15660482-A-T

Variant names:

• chr1-15660482-A-T
• rs142452950
• NM_006511.3:c.614A>T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006511.3(RSC1A1):​c.614A>T​(p.Asn205Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,096 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0028 (10 hom.)
• Consequence: RSC1A1 NM_006511.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0720

Genes affected

RSC1A1 (HGNC:10458): (regulator of solute carriers 1) The protein encoded by this intronless gene inhibits the expression of the solute carrier family 5 (sodium/glucose cotransporter), member 1 gene (SLC5A1) and downregulates exocytosis of the SLC5A1 protein. The encoded protein is sometimes found coating the trans-Golgi network and other times is localized to the nucleus, depending on the cell cycle stage. This protein also inhibits the expression of solute carrier family 22 (organic cation transporter), member 2 (SLC22A2). [provided by RefSeq, Dec 2015]

DDI2 (HGNC:24578): (DNA damage inducible 1 homolog 2) Enables aspartic-type endopeptidase activity; identical protein binding activity; and ubiquitin binding activity. Involved in several processes, including cellular response to hydroxyurea; proteolysis; and regulation of DNA stability. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006115496).
• BS2: High Homozygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSC1A1	NM_006511.3	c.614A>T	p.Asn205Ile	missense_variant	Exon 1 of 1	ENST00000345034.2	NP_006502.1
DDI2	NM_032341.5	c.*692A>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000480945.6	NP_115717.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSC1A1	ENST00000345034.2	c.614A>T	p.Asn205Ile	missense_variant	Exon 1 of 1	6	NM_006511.3	ENSP00000341963.1
DDI2	ENST00000480945.6	c.*692A>T		3_prime_UTR_variant	Exon 10 of 10	2	NM_032341.5	ENSP00000417748.1

Frequencies

GnomAD3 genomes AF: 0.00194 AC: 295 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00190 AC: 475 AN: 250534 Hom.: 0 AF XY: 0.00189 AC XY: 256 AN XY: 135394

Gnomad AFR exome AF: 0.000555

Gnomad AMR exome AF: 0.000696

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000753

Gnomad FIN exome AF: 0.00176

Gnomad NFE exome AF: 0.00311

Gnomad OTH exome AF: 0.00246

GnomAD4 exome AF: 0.00283 AC: 4131 AN: 1461724 Hom.: 10 Cov.: 32 AF XY: 0.00273 AC XY: 1988 AN XY: 727138

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.00146

Gnomad4 NFE exome AF: 0.00338

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00194 AC: 295 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.00166 AC XY: 124 AN XY: 74522

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00344

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00309 Hom.: 0

Bravo AF: 0.00167

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.00185 AC: 224

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00365

EpiControl AF: 0.00273

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.614A>T (p.N205I) alteration is located in exon 1 (coding exon 1) of the RSC1A1 gene. This alteration results from a A to T substitution at nucleotide position 614, causing the asparagine (N) at amino acid position 205 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.53	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.044
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.022	D
Polyphen		0.69	P
Vest4		0.21
MVP		0.37
MPC		0.17
ClinPred		0.021	T
GERP RS		0.79
Varity_R		0.13
gMVP		0.12

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: rs142452950; hg19: chr1-15986977;