1-174241529-T-C

Variant names:

• chr1-174241529-T-C
• NM_001366446.1:c.589T>C

Variant summary

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

The NM_001366446.1(RABGAP1L):​c.589T>C​(p.Tyr197His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y197C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RABGAP1L NM_001366446.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RABGAP1L	NM_001366446.1	c.589T>C	p.Tyr197His	missense_variant	Exon 5 of 26	ENST00000681986.1	NP_001353375.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RABGAP1L	ENST00000681986.1	c.589T>C	p.Tyr197His	missense_variant	Exon 5 of 26		NM_001366446.1	ENSP00000507884.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.589T>C (p.Y197H) alteration is located in exon 1 (coding exon 1) of the RABGAP1L gene. This alteration results from a T to C substitution at nucleotide position 589, causing the tyrosine (Y) at amino acid position 197 to be replaced by a histidine (H). 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	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.011	.;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.3	N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.28	T;T;T
Sift4G	Uncertain	0.059	T;T;T
Polyphen		1.0	D;D;.
Vest4		0.90
MutPred		0.46		.;Loss of catalytic residue at Y197 (P = 0.0321);Loss of catalytic residue at Y197 (P = 0.0321);
MVP		0.52
MPC		0.36
ClinPred		0.93	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.55
Mutation Taster		=210/90	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr1-174210667;