rs113418909

Variant names:

• chr14-94314305-A-T
• rs113418909
• NM_001756.4:c.344T>A

Your query was ambiguous. Multiple possible variants found:

• chr14-94314305-A-T
• chr14-94314305-A-G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001756.4(SERPINA6):​c.344T>A​(p.Leu115His) variant causes a missense change. The variant allele was found at a frequency of 0.00246 in 1,614,130 control chromosomes in the GnomAD database, including 3 homozygotes. 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 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (2 hom.)
• Consequence: SERPINA6 NM_001756.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:2 B:1
• Conservation: PhyloP100: 5.41
• Publications: 19 publications found

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]

SERPINA6 Gene-Disease associations (from GenCC):

• corticosteroid-binding globulin deficiency

  Inheritance: AR, AD, SD, Unknown Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia, Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014943153).
• BS2: High Homozygotes in GnomAdExome4 at 2 SD,Unknown,AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001756.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA6	NM_001756.4	MANE Select	c.344T>A	p.Leu115His	missense	Exon 2 of 5	NP_001747.3	P08185

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA6	ENST00000341584.4	TSL:1 MANE Select	c.344T>A	p.Leu115His	missense	Exon 2 of 5	ENSP00000342850.3	P08185
	SERPINA6	ENST00000874318.1		c.344T>A	p.Leu115His	missense	Exon 2 of 5	ENSP00000544377.1
	SERPINA6	ENST00000874321.1		c.344T>A	p.Leu115His	missense	Exon 2 of 6	ENSP00000544380.1

Frequencies

GnomAD3 genomes AF: 0.00218 AC: 332 AN: 152122 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00383

GnomAD2 exomes AF: 0.00223 AC: 560 AN: 251354 AF XY: 0.00244

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00194

Gnomad NFE exome AF: 0.00333

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00249 AC: 3638 AN: 1461890 Hom.: 2 Cov.: 32 AF XY: 0.00246 AC XY: 1786 AN XY: 727246

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00114 AC: 51 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00140 AC: 121 AN: 86258

European-Finnish (FIN) AF: 0.00219 AC: 117 AN: 53416

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.00283 AC: 3142 AN: 1112012

Other (OTH) AF: 0.00194 AC: 117 AN: 60396

GnomAD4 genome AF: 0.00218 AC: 332 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.00226 AC XY: 168 AN XY: 74432

African (AFR) AF: 0.000361 AC: 15 AN: 41546

American (AMR) AF: 0.00124 AC: 19 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4816

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00360 AC: 245 AN: 68016

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00333 Hom.: 1

Bravo AF: 0.00210

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00468

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	1	-	not provided (3)
2	-	-	Corticosteroid-binding globulin deficiency (2)
-	-	1	not specified (1)
-	1	-	SERPINA6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.15
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.4
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.030	D
Polyphen		0.88	P
Vest4		0.47
MVP		0.90
MPC		0.31
ClinPred		0.062	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.53
gMVP		0.22
Mutation Taster		=57/43	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

Other links and lift over

dbSNP: rs113418909; hg19: chr14-94780642;