14-94304471-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001756.4(SERPINA6):c.1165G>A(p.Asp389Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000358 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (0 hom.)
• Consequence: SERPINA6 NM_001756.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 3.96

Genes affected

SERPINA6 (HGNC:1540): (serpin family A member 6) This gene encodes an alpha-globulin protein with corticosteroid-binding properties. This is the major transport protein for glucorticoids and progestins in the blood of most vertebrates. The gene localizes to a chromosomal region containing several closely related serine protease inhibitors which may have evolved by duplication events. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 14-94304471-C-T is Pathogenic according to our data. Variant chr14-94304471-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 16975.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr14-94304471-C-T is described in UniProt as null. Variant chr14-94304471-C-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.013436496).. Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SERPINA6	NM_001756.4	c.1165G>A	p.Asp389Asn	missense_variant	5/5	ENST00000341584.4
SERPINA6	XM_047431827.1	c.1336G>A	p.Asp446Asn	missense_variant	5/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SERPINA6	ENST00000341584.4	c.1165G>A	p.Asp389Asn	missense_variant	5/5	1	NM_001756.4	P1
SERPINA6	ENST00000555056.1	c.*477G>A		3_prime_UTR_variant, NMD_transcript_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.000507 AC: 77 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000617 AC: 155 AN: 251322 Hom.: 0 AF XY: 0.000567 AC XY: 77 AN XY: 135852

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000781

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000343

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000343 AC: 501 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.000355 AC XY: 258 AN XY: 727248

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.00704

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000190

Gnomad4 OTH exome AF: 0.000778

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35 AN XY: 74368

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000483 Hom.: 0

Bravo AF: 0.000612

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000511 AC: 62

EpiCase AF: 0.000273

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Corticosteroid-binding globulin deficiency Pathogenic:3 Uncertain:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 12, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Jan 30, 2020	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001756.3:c.1165G>A in the SERPINA6 gene has an allele frequency of 0.007 in Ashkenazi Jewish subpopulation in the gnomAD database. It was detected in individual with autosomal recessive Corticosteroid-binding globulin deficiency, two homozygous c.1165G>A(PMID: 12780753; 20610591). Co-segregation evidence in a pedigree, two patients were affected and one sibling unaffected (PMID: 20610591). Pathogenic computational verdict because 9 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster and REVEL. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP criteria applied: PP1_Moderate; PM3; PP4; PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 26, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.18
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.2	M
MutationTaster	Benign	1.0	A
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.52
Sift	Benign	0.37	T
Sift4G	Benign	0.15	T
Polyphen		0.98	D
Vest4		0.36
MVP		0.91
MPC		0.45
ClinPred		0.17	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.73
gMVP		0.68

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: rs28929488; hg19: chr14-94770808;