11-7509478-G-T

Position:

• chr11-7509478-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_198474.4(OLFML1):​c.499G>T​(p.Asp167Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OLFML1 NM_198474.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.52

Genes affected

OLFML1 (HGNC:24473): (olfactomedin like 1) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

LOC124902806 (HGNC:):

SYT9-AS1 (HGNC:56173): (SYT9 antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OLFML1	NM_198474.4	c.499G>T	p.Asp167Tyr	missense_variant	3/3	ENST00000329293.4	NP_940876.2
LOC124902806	XM_047428005.1	c.*1088-1295C>A		intron_variant			XP_047283961.1
OLFML1	NM_001370498.1	c.499G>T	p.Asp167Tyr	missense_variant	4/4		NP_001357427.1
OLFML1	NM_001370499.1	c.91G>T	p.Asp31Tyr	missense_variant	3/3		NP_001357428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OLFML1	ENST00000329293.4	c.499G>T	p.Asp167Tyr	missense_variant	3/3	1	NM_198474.4	ENSP00000332511	P1
SYT9-AS1	ENST00000530201.2	n.1350+2645C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 28, 2022

The c.499G>T (p.D167Y) alteration is located in exon 3 (coding exon 3) of the OLFML1 gene. This alteration results from a G to T substitution at nucleotide position 499, causing the aspartic acid (D) at amino acid position 167 to be replaced by a tyrosine (Y). 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	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	.;T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-7.9	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.96		Loss of ubiquitination at K166 (P = 0.0481);Loss of ubiquitination at K166 (P = 0.0481);
MVP		0.94
MPC		0.18
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.92
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-7530709;