6-2953157-A-C

Variant names:

• chr6-2953157-A-C
• rs727503416
• NM_004568.6:c.460T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_004568.6(SERPINB6):​c.460T>G​(p.Ser154Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,614,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S154P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: SERPINB6 NM_004568.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.98

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-2953157-A-C is Benign according to our data. Variant chr6-2953157-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 165189.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr6-2953157-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SERPINB6	NM_004568.6	c.460T>G	p.Ser154Ala	missense_variant	Exon 5 of 7	ENST00000380539.7	NP_004559.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SERPINB6	ENST00000380539.7	c.460T>G	p.Ser154Ala	missense_variant	Exon 5 of 7	3	NM_004568.6	ENSP00000369912.2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251482 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000280 AC: 41 AN: 1461886 Hom.: 0 Cov.: 67 AF XY: 0.0000330 AC XY: 24 AN XY: 727240

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86258

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53414

Gnomad4 NFE exome AF: 0.0000342 AC: 38 AN: 1112010

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152224 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000735 AC: 0.0000734862 AN: 0.0000734862

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 154 of the SERPINB6 protein (p.Ser154Ala). This variant is present in population databases (rs727503416, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of SERPINB6-related conditions (PMID: 20451170). ClinVar contains an entry for this variant (Variation ID: 165189). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt SERPINB6 protein function with a negative predictive value of 80%. 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. -

not specified Benign:1

Jun 12, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ser154Ala in exon 8 of SERPINB6: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, chinchilla, brush-tailed rat, and manatee have an alanine (Ala) at this p osition, despite high nearby amino acid conservation. In addition, computationa l prediction tools do not suggest a high likelihood of impact to the protein. Th is variant was previously identified in an individual with hearing loss; however , the variant was in the heterozygous state and a variant affecting the remainin g copy of SERPINB6 was not identified (Sirmaci 2010). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.35
DANN	Benign	0.46
DEOGEN2	Benign	0.17	T;T;T;T;T;T;T;T;T;.;T;T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.51	.;.;.;.;.;.;.;T;.;T;.;T;T;T
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.49	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M;M;.;.;.;M;M;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;N;N;N;.;N;.;.;.;.;.;N;.;.
REVEL	Benign	0.28
Sift	Benign	0.16	T;T;T;T;.;T;.;.;.;.;.;T;.;.
Sift4G	Benign	0.14	T;T;T;T;.;T;.;T;.;.;.;T;.;.
Polyphen		0.024	B;B;B;B;B;B;B;.;.;.;B;B;.;.
Vest4		0.048
MutPred		0.63		Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);.;.;.;Loss of disorder (P = 0.0815);Loss of disorder (P = 0.0815);.;.;
MVP		0.60
MPC		0.083
ClinPred		0.063	T
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.060
gMVP		0.29
Mutation Taster		=98/2	polymorphism

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: rs727503416; hg19: chr6-2953391;