rs750740230

Variant names:

• chr5-16616966-C-G
• rs750740230
• NM_001034850.3:c.6G>C

Your query was ambiguous. Multiple possible variants found:

• chr5-16616966-C-G
• chr5-16616966-C-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6 BP7 BS1

The NM_001034850.3(RETREG1):​c.6G>C​(p.Ala2Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000644 in 1,429,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: RETREG1 NM_001034850.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

Genes affected

RETREG1 (HGNC:25964): (reticulophagy regulator 1) The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

RETREG1-AS1 (HGNC:55551): (RETREG1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-16616966-C-G is Benign according to our data. Variant chr5-16616966-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 352698.
• BP7: Synonymous conserved (PhyloP=1.16 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000409 (62/151688) while in subpopulation NFE AF = 0.000618 (42/67908). AF 95% confidence interval is 0.00047. There are 0 homozygotes in GnomAd4. There are 31 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001034850.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	NM_001034850.3	MANE Select	c.6G>C	p.Ala2Ala	synonymous	Exon 1 of 9	NP_001030022.1
	RETREG1-AS1	NR_109946.1		n.561+480C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RETREG1	ENST00000306320.10	TSL:1 MANE Select	c.6G>C	p.Ala2Ala	synonymous	Exon 1 of 9	ENSP00000304642.9
	RETREG1	ENST00000682229.1		c.6G>C	p.Ala2Ala	synonymous	Exon 1 of 10	ENSP00000507342.1
	RETREG1	ENST00000682564.1		c.6G>C	p.Ala2Ala	synonymous	Exon 1 of 9	ENSP00000508099.1

Frequencies

GnomAD3 genomes AF: 0.000409 AC: 62 AN: 151688 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000218

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000618

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000341 AC: 21 AN: 61560 AF XY: 0.000335

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000436

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000696

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000672 AC: 859 AN: 1277478 Hom.: 0 Cov.: 29 AF XY: 0.000674 AC XY: 423 AN XY: 627642

African (AFR) AF: 0.0000777 AC: 2 AN: 25726

American (AMR) AF: 0.000447 AC: 10 AN: 22396

Ashkenazi Jewish (ASJ) AF: 0.0000465 AC: 1 AN: 21524

East Asian (EAS) AF: 0.00 AC: 0 AN: 27542

South Asian (SAS) AF: 0.00 AC: 0 AN: 66390

European-Finnish (FIN) AF: 0.0000948 AC: 3 AN: 31640

Middle Eastern (MID) AF: 0.000531 AC: 2 AN: 3766

European-Non Finnish (NFE) AF: 0.000787 AC: 807 AN: 1025920

Other (OTH) AF: 0.000647 AC: 34 AN: 52574

GnomAD4 genome AF: 0.000409 AC: 62 AN: 151688 Hom.: 0 Cov.: 32 AF XY: 0.000419 AC XY: 31 AN XY: 74066

African (AFR) AF: 0.000218 AC: 9 AN: 41376

American (AMR) AF: 0.000525 AC: 8 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000618 AC: 42 AN: 67908

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000465

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	1	-	Neuropathy, hereditary sensory and autonomic, type 2B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	16
DANN	Benign	0.69
PhyloP100		1.2
PromoterAI		-0.30	Neutral
Mutation Taster		=100/0	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: rs750740230; hg19: chr5-16617075;