chr19-38307723-G-T

Position:

• chr19-38307723-G-T

Variant summary

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

The NM_001039672.3(YIF1B):​c.569C>A​(p.Ala190Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,460,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: YIF1B NM_001039672.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.37

Genes affected

YIF1B (HGNC:30511): (Yip1 interacting factor homolog B, membrane trafficking protein) Predicted to be involved in endoplasmic reticulum to Golgi vesicle-mediated transport; protein targeting to membrane; and sperm axoneme assembly. Located in Golgi apparatus; endoplasmic reticulum; and endoplasmic reticulum-Golgi intermediate compartment. [provided by Alliance of Genome Resources, Apr 2022]

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, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
YIF1B	NM_001039672.3	c.569C>A	p.Ala190Glu	missense_variant	6/8	ENST00000339413.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
YIF1B	ENST00000339413.11	c.569C>A	p.Ala190Glu	missense_variant	6/8	1	NM_001039672.3	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460944 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726776

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2020

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	.;.;.;T;T;.;.;.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D;.;D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Pathogenic	3.3	.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.5	.;D;D;D;.;D;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	.;D;D;D;.;D;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;.
Polyphen		1.0	D;D;D;D;.;.;D;D;.
Vest4		0.96
MutPred		0.82		.;.;.;Gain of disorder (P = 0.0444);.;.;.;.;.;
MVP		0.86
MPC		1.3
ClinPred		0.99	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.84
gMVP		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1039243015; hg19: chr19-38798363;