chr1-174219254-G-A

Variant names:

• chr1-174219254-G-A
• rs1669570882
• NM_001366446.1:c.97G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366446.1(RABGAP1L):​c.97G>A​(p.Asp33Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,595,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RABGAP1L NM_001366446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

RABGAP1L (HGNC:24663): (RAB GTPase activating protein 1 like) Enables GTPase activator activity and small GTPase binding activity. Acts upstream of or within regulation of protein localization. Located in Golgi apparatus; early endosome; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17478856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABGAP1L	NM_001366446.1	c.97G>A	p.Asp33Asn	missense_variant	Exon 2 of 26	ENST00000681986.1	NP_001353375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABGAP1L	ENST00000681986.1	c.97G>A	p.Asp33Asn	missense_variant	Exon 2 of 26		NM_001366446.1	ENSP00000507884.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1443078 Hom.: 0 Cov.: 31 AF XY: 0.00000418 AC XY: 3 AN XY: 716944

African (AFR) AF: 0.0000305 AC: 1 AN: 32800

American (AMR) AF: 0.00 AC: 0 AN: 42790

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39032

South Asian (SAS) AF: 0.00 AC: 0 AN: 81936

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102102

Other (OTH) AF: 0.0000167 AC: 1 AN: 59708

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74284

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.0000656 AC: 1 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 29, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.97G>A (p.D33N) alteration is located in exon 1 (coding exon 1) of the RABGAP1L gene. This alteration results from a G to A substitution at nucleotide position 97, causing the aspartic acid (D) at amino acid position 33 to be replaced by an asparagine (N). 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	0.068
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	T;.
Eigen	Benign	0.071
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M;.
PhyloP100		3.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.26	N;N
REVEL	Benign	0.059
Sift	Benign	0.10	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.47	P;.
Vest4		0.18
MutPred		0.36		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.53
MPC		0.26
ClinPred		0.51	D
GERP RS		4.1
Varity_R		0.16
gMVP		0.22
Mutation Taster		=92/8	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: rs1669570882; hg19: chr1-174188392;