14-94464715-C-T

Variant names:

• chr14-94464715-C-T
• rs77274019
• NM_175739.4:c.1042G>A

Variant summary

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

The NM_175739.4(SERPINA9):​c.1042G>A​(p.Val348Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00284 in 1,612,306 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V348L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0023 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: SERPINA9 NM_175739.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.578
• Publications: 7 publications found

Genes affected

SERPINA9 (HGNC:15995): (serpin family A member 9) Enables serine-type endopeptidase inhibitor activity. Predicted to be involved in negative regulation of endopeptidase activity. Predicted to be located in cytoplasm and membrane. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000256357 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009540707).
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175739.4. 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
	SERPINA9	NM_175739.4	MANE Select	c.1042G>A	p.Val348Ile	missense	Exon 4 of 5	NP_783866.3	Q86WD7-1
	SERPINA9	NM_001284275.2		c.802G>A	p.Val268Ile	missense	Exon 4 of 5	NP_001271204.2	Q86WD7-6
	SERPINA9	NM_001042518.2		c.742G>A	p.Val248Ile	missense	Exon 5 of 6	NP_001035983.2	A0A6Q8JH89

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA9	ENST00000674397.2	MANE Select	c.1042G>A	p.Val348Ile	missense	Exon 4 of 5	ENSP00000501517.1	Q86WD7-1
	SERPINA9	ENST00000337425.10	TSL:1	c.1096G>A	p.Val366Ile	missense	Exon 4 of 5	ENSP00000337133.5	Q86WD7-7
	SERPINA9	ENST00000448305.6	TSL:1	c.802G>A	p.Val268Ile	missense	Exon 4 of 5	ENSP00000414092.2	Q86WD7-6

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152176 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00406

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00395

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00240 AC: 595 AN: 248048 AF XY: 0.00233

Gnomad AFR exome AF: 0.000388

Gnomad AMR exome AF: 0.000234

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00423

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.00289 AC: 4225 AN: 1460012 Hom.: 12 Cov.: 32 AF XY: 0.00279 AC XY: 2027 AN XY: 726298

African (AFR) AF: 0.000269 AC: 9 AN: 33416

American (AMR) AF: 0.000180 AC: 8 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26044

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85864

European-Finnish (FIN) AF: 0.00479 AC: 256 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00343 AC: 3813 AN: 1111096

Other (OTH) AF: 0.00222 AC: 134 AN: 60338

GnomAD4 genome AF: 0.00227 AC: 346 AN: 152294 Hom.: 0 Cov.: 34 AF XY: 0.00232 AC XY: 173 AN XY: 74464

African (AFR) AF: 0.000577 AC: 24 AN: 41574

American (AMR) AF: 0.000392 AC: 6 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00406 AC: 43 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00395 AC: 269 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00270 Hom.: 3

Bravo AF: 0.00165

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000551 AC: 2

ESP6500EA AF: 0.00405 AC: 33

ExAC AF: 0.00279 AC: 337

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00267

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	14
DANN	Benign	0.73
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0095	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.58
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.17
Sift	Benign	0.060	T
Sift4G	Benign	0.31	T
Polyphen		0.0030	B
Vest4		0.058
MVP		0.10
MPC		0.017
ClinPred		0.0061	T
GERP RS		0.84
Varity_R		0.046
gMVP		0.066
Mutation Taster		=100/0	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: rs77274019; hg19: chr14-94931052;