rs148530934

chr6-2954708-G-T

Variant summary

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

The NM_004568.6(SERPINB6):c.314C>A(p.Ser105Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000632 in 1,608,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00065 (0 hom.)
• Consequence: SERPINB6 NM_004568.6 missense, splice_region
• Scores: Splicing: ADA: 0.004642
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 0.159

Genes affected

SERPINB6 (HGNC:8950): (serpin family B member 6) The protein encoded by this gene is a member of the serpin (serine proteinase inhibitor) superfamily, and ovalbumin(ov)-serpin subfamily. It was originally discovered as a placental thrombin inhibitor. The mouse homolog was found to be expressed in the hair cells of the inner ear. Mutations in this gene are associated with nonsyndromic progressive hearing loss, suggesting that this serpin plays an important role in the inner ear in the protection against leakage of lysosomal content during stress, and that loss of this protection results in cell death and sensorineural hearing loss. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Sep 2010]

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=0.09161574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINB6	NM_004568.6	c.314C>A	p.Ser105Tyr	missense_variant, splice_region_variant	4/7	ENST00000380539.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINB6	ENST00000380539.7	c.314C>A	p.Ser105Tyr	missense_variant, splice_region_variant	4/7	3	NM_004568.6	P1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000838

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000461 AC: 116 AN: 251358 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135858

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000647 AC: 942 AN: 1456036 Hom.: 0 Cov.: 28 AF XY: 0.000624 AC XY: 452 AN XY: 724750

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000794

Gnomad4 OTH exome AF: 0.000631

GnomAD4 genome AF: 0.000493 AC: 75 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74440

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000838

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000711 Hom.: 1

Bravo AF: 0.000533

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000494 AC: 60

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 25, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 17, 2022	This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 105 of the SERPINB6 protein (p.Ser105Tyr). This variant is present in population databases (rs148530934, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with SERPINB6-related conditions. ClinVar contains an entry for this variant (Variation ID: 229240). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 22, 2023	BS1_supporting -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2021	The c.314C>A (p.S105Y) alteration is located in exon 4 (coding exon 3) of the SERPINB6 gene. This alteration results from a C to A substitution at nucleotide position 314, causing the serine (S) at amino acid position 105 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 13, 2017	The p.Ser105Tyr variant in SERPINB6 has been previously reported by our laborato ry in the heterozygous state in two individuals with hearing loss. It has also been identified in 0.1% (102/126684) of European chromosomes by the Genome Aggre gation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs148530934). A lthough this variant has been seen in the general population, its frequency is n ot high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Ser105Tyr variant i s uncertain. -

Usher syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, PP3_Supporting, BP5_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;D;D;D;D;D;D;T;T;.;D;D;T;.;.
Eigen	Uncertain	0.33
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.70	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.092	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.0014	T
MutationAssessor	Pathogenic	3.2	M;M;M;M;M;M;M;.;.;.;M;M;.;.;.
MutationTaster	Benign	0.89	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.6	D;D;D;D;.;D;.;.;.;.;.;D;.;.;.
REVEL	Uncertain	0.40
Sift	Uncertain	0.011	D;D;D;D;.;D;.;.;.;.;.;D;.;.;.
Sift4G	Uncertain	0.014	D;D;D;D;.;D;.;D;.;.;.;D;.;.;.
Polyphen		1.0	D;D;D;D;D;D;D;.;.;.;D;D;.;.;.
Vest4		0.31
MVP		0.94
MPC		0.56
ClinPred		0.12	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.15
SpliceAI score (max)		0.16		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: rs148530934; hg19: chr6-2954942;