rs201123081

Variant names:

• chr12-47757977-C-T
• rs201123081
• NM_001098531.4:c.108G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6_Moderate BP7

The NM_001098531.4(RAPGEF3):​c.108G>A​(p.Pro36Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000287 in 1,566,716 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: RAPGEF3 NM_001098531.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.59

Genes affected

RAPGEF3 (HGNC:16629): (Rap guanine nucleotide exchange factor 3) Enables guanyl-nucleotide exchange factor activity and protein domain specific binding activity. Involved in several processes, including positive regulation of protein modification process; regulation of actin cytoskeleton organization; and regulation of syncytium formation by plasma membrane fusion. Located in filopodium; lamellipodium; and microvillus. Colocalizes with cortical actin cytoskeleton and plasma membrane. Biomarker of congestive heart failure. [provided by Alliance of Genome Resources, Apr 2022]

SLC48A1 (HGNC:26035): (solute carrier family 48 member 1) Enables heme binding activity and heme transmembrane transporter activity. Involved in heme transport. Located in endosome membrane; lysosomal membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-47757977-C-T is Benign according to our data. Variant chr12-47757977-C-T is described in ClinVar as [Benign]. Clinvar id is 714536.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.59 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAPGEF3	NM_001098531.4	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 2 of 28	ENST00000449771.7	NP_001092001.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAPGEF3	ENST00000449771.7	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 2 of 28	2	NM_001098531.4	ENSP00000395708.2
RAPGEF3	ENST00000389212.7	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 3 of 29	2		ENSP00000373864.3
RAPGEF3	ENST00000395358.7	c.108G>A	p.Pro36Pro	synonymous_variant	Exon 2 of 16	2		ENSP00000378764.3
RAPGEF3	ENST00000549151.5	c.-19G>A		5_prime_UTR_variant	Exon 2 of 28	5		ENSP00000448619.1
RAPGEF3	ENST00000548919.5	c.-19G>A		5_prime_UTR_variant	Exon 2 of 27	2		ENSP00000448480.1
RAPGEF3	ENST00000547856.5	n.108G>A		non_coding_transcript_exon_variant	Exon 2 of 24	2		ENSP00000449905.1

Frequencies

GnomAD3 genomes AF: 0.00153 AC: 233 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000351 AC: 62 AN: 176752 AF XY: 0.000255

Gnomad AFR exome AF: 0.00406

Gnomad AMR exome AF: 0.000667

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 215 AN: 1414416 Hom.: 1 Cov.: 31 AF XY: 0.000144 AC XY: 101 AN XY: 699152

African (AFR) AF: 0.00475 AC: 154 AN: 32436

American (AMR) AF: 0.000501 AC: 19 AN: 37932

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25272

East Asian (EAS) AF: 0.0000807 AC: 3 AN: 37194

South Asian (SAS) AF: 0.0000249 AC: 2 AN: 80412

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49808

Middle Eastern (MID) AF: 0.000363 AC: 2 AN: 5516

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1087250

Other (OTH) AF: 0.000393 AC: 23 AN: 58596

GnomAD4 genome AF: 0.00154 AC: 235 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.00152 AC XY: 113 AN XY: 74478

African (AFR) AF: 0.00534 AC: 222 AN: 41566

American (AMR) AF: 0.000849 AC: 13 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000834 Hom.: 1

Bravo AF: 0.00178

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	1.2
DANN	Benign	0.91
PhyloP100		-3.6
PromoterAI		-0.025	Neutral
Mutation Taster		=297/3	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

Publications

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Other links and lift over

dbSNP: rs201123081; hg19: chr12-48151760;