chr2-188529160-A-G

Position:

• chr2-188529160-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016315.4(GULP1):​c.226A>G​(p.Ile76Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000014 in 1,432,802 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GULP1 NM_016315.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

Genes affected

GULP1 (HGNC:18649): (GULP PTB domain containing engulfment adaptor 1) The protein encoded by this gene is an adapter protein necessary for the engulfment of apoptotic cells by phagocytes. Several transcript variants, some protein coding and some thought not to be protein coding, have been found for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25015384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GULP1	NM_016315.4	c.226A>G	p.Ile76Val	missense_variant	6/12	ENST00000409830.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GULP1	ENST00000409830.6	c.226A>G	p.Ile76Val	missense_variant	6/12	1	NM_016315.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000288 AC: 7 AN: 243362 Hom.: 0 AF XY: 0.0000380 AC XY: 5 AN XY: 131662

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000612

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.0000354

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000269

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000140 AC: 20 AN: 1432802 Hom.: 0 Cov.: 25 AF XY: 0.0000112 AC XY: 8 AN XY: 713800

Gnomad4 AFR exome AF: 0.0000306

Gnomad4 AMR exome AF: 0.0000465

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000138

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000264

ExAC AF: 0.0000330 AC: 4

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

Dec 15, 2023

The c.226A>G (p.I76V) alteration is located in exon 6 (coding exon 4) of the GULP1 gene. This alteration results from a A to G substitution at nucleotide position 226, causing the isoleucine (I) at amino acid position 76 to be replaced by a valine (V). 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	0.21
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.036	.;T;.;T;T;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;.;.;.;D;D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.25	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.41	N;N;N;N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	0.080	N;N;N;N;N;N;N
REVEL	Benign	0.24
Sift	Benign	0.52	T;T;T;T;T;T;T
Sift4G	Benign	0.65	T;T;T;T;T;T;T
Polyphen		0.98, 0.95	.;D;P;D;D;P;D
Vest4		0.44
MutPred		0.51		Loss of catalytic residue at I76 (P = 0.0085);Loss of catalytic residue at I76 (P = 0.0085);Loss of catalytic residue at I76 (P = 0.0085);Loss of catalytic residue at I76 (P = 0.0085);Loss of catalytic residue at I76 (P = 0.0085);Loss of catalytic residue at I76 (P = 0.0085);Loss of catalytic residue at I76 (P = 0.0085);
MVP		0.36
MPC		0.65
ClinPred		0.23	T
GERP RS		5.5
Varity_R		0.19
gMVP		0.23

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs777255415; hg19: chr2-189393887;