5-64718012-T-C

Variant names:

• chr5-64718012-T-C
• rs780755616
• NM_001164442.2:c.473T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001164442.2(SHISAL2B):​c.473T>C​(p.Ile158Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000746 in 1,352,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: SHISAL2B NM_001164442.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.04

Genes affected

SHISAL2B (HGNC:34236): (shisa like 2B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

SREK1IP1 (HGNC:26716): (SREK1 interacting protein 1) Predicted to enable nucleic acid binding activity and zinc ion binding activity. Predicted to be involved in RNA splicing and mRNA processing. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.058463335).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SHISAL2B	NM_001164442.2	c.473T>C	p.Ile158Thr	missense_variant	Exon 3 of 3	ENST00000389074.6	NP_001157914.1
SREK1IP1	NM_173829.4	c.*6372A>G		downstream_gene_variant		ENST00000513458.9	NP_776190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SHISAL2B	ENST00000389074.6	c.473T>C	p.Ile158Thr	missense_variant	Exon 3 of 3	2	NM_001164442.2	ENSP00000373726.5
SREK1IP1	ENST00000513458.9	c.*6372A>G		downstream_gene_variant		1	NM_173829.4	ENSP00000427401.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000625 AC: 7 AN: 112062 Hom.: 0 AF XY: 0.0000662 AC XY: 4 AN XY: 60450

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000247

Gnomad SAS exome AF: 0.000255

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000195

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000746 AC: 101 AN: 1352984 Hom.: 0 Cov.: 30 AF XY: 0.0000809 AC XY: 54 AN XY: 667352

Gnomad4 AFR exome AF: 0.000136

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000867

Gnomad4 SAS exome AF: 0.000166

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000747

Gnomad4 OTH exome AF: 0.0000354

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.000133 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.473T>C (p.I158T) alteration is located in exon 3 (coding exon 3) of the FAM159B gene. This alteration results from a T to C substitution at nucleotide position 473, causing the isoleucine (I) at amino acid position 158 to be replaced by a threonine (T). 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	0.060
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	12
DANN	Benign	0.64
DEOGEN2	Benign	0.00028	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.058	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.034
Sift	Benign	0.31	T
Sift4G	Benign	0.56	T
Vest4		0.13
MutPred		0.22		Gain of disorder (P = 0.0264);
MVP		0.030
MPC		0.13
ClinPred		0.036	T
GERP RS		-3.1
Varity_R		0.033
gMVP		0.089

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

LitVar

Other links and lift over

dbSNP: rs780755616; hg19: chr5-64013839;