chr5-131431345-T-C

Position:

• chr5-131431345-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016340.6(RAPGEF6):​c.3979A>G​(p.Thr1327Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000687 in 1,587,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: RAPGEF6 NM_016340.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0790

Genes affected

RAPGEF6 (HGNC:20655): (Rap guanine nucleotide exchange factor 6) Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000273217 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.024527013).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RAPGEF6	NM_016340.6	c.3979A>G	p.Thr1327Ala	missense_variant	26/28	ENST00000509018.6	NP_057424.3
RAPGEF6	NM_001164386.2	c.4003A>G	p.Thr1335Ala	missense_variant	27/29		NP_001157858.1
RAPGEF6	NM_001164387.2	c.4018A>G	p.Thr1340Ala	missense_variant	28/29		NP_001157859.1
RAPGEF6	NM_001164388.2	c.4003A>G	p.Thr1335Ala	missense_variant	27/28		NP_001157860.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RAPGEF6	ENST00000509018.6	c.3979A>G	p.Thr1327Ala	missense_variant	26/28	1	NM_016340.6	ENSP00000421684.1
ENSG00000273217	ENST00000514667.1	c.4129A>G	p.Thr1377Ala	missense_variant	27/29	2		ENSP00000426948.1

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000970 AC: 23 AN: 237078 Hom.: 0 AF XY: 0.000101 AC XY: 13 AN XY: 129144

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000503

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000652

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000655 AC: 94 AN: 1434804 Hom.: 0 Cov.: 34 AF XY: 0.0000776 AC XY: 55 AN XY: 709210

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000622

Gnomad4 OTH exome AF: 0.000102

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000129 Hom.: 0

Bravo AF: 0.000166

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.0000546

EpiControl AF: 0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 18, 2024

The c.4003A>G (p.T1335A) alteration is located in exon 27 (coding exon 27) of the RAPGEF6 gene. This alteration results from a A to G substitution at nucleotide position 4003, causing the threonine (T) at amino acid position 1335 to be replaced by an alanine (A). 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	0.069
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	15
DANN	Benign	0.29
DEOGEN2	Benign	0.12	T;.;.;.;.
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.52	T;T;T;T;T
M_CAP	Benign	0.0017	T
MetaRNN	Benign	0.025	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.27	N;.;N;.;N
REVEL	Benign	0.037
Sift	Benign	0.42	T;.;T;.;T
Sift4G	Benign	0.60	T;T;T;T;T
Polyphen		0.0010	B;B;.;.;.
Vest4		0.032
MVP		0.27
MPC		0.16, 0.16
ClinPred		0.044	T
GERP RS		-2.3
Varity_R		0.012
gMVP		0.15

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: rs141687018; hg19: chr5-130767038;