rs6647

Variant names:

• chr14-94381078-A-G
• rs6647
• NM_000295.5:c.710T>C

Your query was ambiguous. Multiple possible variants found:

• chr14-94381078-A-G
• chr14-94381078-A-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000295.5(SERPINA1):​c.710T>C​(p.Val237Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,609,248 control chromosomes in the GnomAD database, including 47,211 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. V237V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (8923 hom., cov: 30)
  • Exomes 𝑓: 0.22 (38288 hom.)
• Consequence: SERPINA1 NM_000295.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.183
• Publications: 64 publications found

Genes affected

SERPINA1 (HGNC:8941): (serpin family A member 1) The protein encoded by this gene is a serine protease inhibitor belonging to the serpin superfamily whose targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, and plasminogen activator. This protein is produced in the liver, the bone marrow, by lymphocytic and monocytic cells in lymphoid tissue, and by the Paneth cells of the gut. Defects in this gene are associated with chronic obstructive pulmonary disease, emphysema, and chronic liver disease. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Aug 2020]

SERPINA1 Gene-Disease associations (from GenCC):

• alpha 1-antitrypsin deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hemorrhagic disease due to alpha-1-antitrypsin Pittsburgh mutation

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7623495E-5).
• BP6: Variant 14-94381078-A-G is Benign according to our data. Variant chr14-94381078-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 17955.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.545 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000295.5. 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
	SERPINA1	NM_000295.5	MANE Select	c.710T>C	p.Val237Ala	missense	Exon 3 of 5	NP_000286.3
	SERPINA1	NM_001002235.3		c.710T>C	p.Val237Ala	missense	Exon 3 of 5	NP_001002235.1	E9KL23
	SERPINA1	NM_001002236.3		c.710T>C	p.Val237Ala	missense	Exon 5 of 7	NP_001002236.1	E9KL23

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SERPINA1	ENST00000393087.9	TSL:1 MANE Select	c.710T>C	p.Val237Ala	missense	Exon 3 of 5	ENSP00000376802.4	P01009-1
	SERPINA1	ENST00000355814.8	TSL:1	c.710T>C	p.Val237Ala	missense	Exon 3 of 5	ENSP00000348068.4	P01009-1
	SERPINA1	ENST00000393088.8	TSL:1	c.710T>C	p.Val237Ala	missense	Exon 5 of 7	ENSP00000376803.4	P01009-1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45061 AN: 151122 Hom.: 8912 Cov.: 30

Gnomad AFR AF: 0.551

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.0209

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.210 AC: 52480 AN: 250450 AF XY: 0.205

Gnomad AFR exome AF: 0.558

Gnomad AMR exome AF: 0.0941

Gnomad ASJ exome AF: 0.259

Gnomad EAS exome AF: 0.0213

Gnomad FIN exome AF: 0.299

Gnomad NFE exome AF: 0.218

Gnomad OTH exome AF: 0.212

GnomAD4 exome AF: 0.216 AC: 315025 AN: 1458008 Hom.: 38288 Cov.: 33 AF XY: 0.213 AC XY: 154538 AN XY: 725512

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.561 AC: 18706 AN: 33354

American (AMR) AF: 0.102 AC: 4546 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6677 AN: 26110

East Asian (EAS) AF: 0.0120 AC: 476 AN: 39700

South Asian (SAS) AF: 0.164 AC: 14144 AN: 86154

European-Finnish (FIN) AF: 0.293 AC: 15553 AN: 53022

Middle Eastern (MID) AF: 0.167 AC: 940 AN: 5634

European-Non Finnish (NFE) AF: 0.217 AC: 240825 AN: 1109066

Other (OTH) AF: 0.218 AC: 13158 AN: 60268

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.298 AC: 45104 AN: 151240 Hom.: 8923 Cov.: 30 AF XY: 0.295 AC XY: 21772 AN XY: 73860

African (AFR) AF: 0.551 AC: 22584 AN: 40998

American (AMR) AF: 0.157 AC: 2397 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 900 AN: 3468

East Asian (EAS) AF: 0.0209 AC: 108 AN: 5158

South Asian (SAS) AF: 0.152 AC: 722 AN: 4756

European-Finnish (FIN) AF: 0.298 AC: 3122 AN: 10468

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14471 AN: 67846

Other (OTH) AF: 0.252 AC: 530 AN: 2100

Alfa AF: 0.235 Hom.: 23061

Bravo AF: 0.299

TwinsUK AF: 0.225 AC: 833

ALSPAC AF: 0.217 AC: 837

ESP6500AA AF: 0.541 AC: 2382

ESP6500EA AF: 0.212 AC: 1821

ExAC AF: 0.221 AC: 26873

Asia WGS AF: 0.100 AC: 351 AN: 3478

EpiCase AF: 0.202

EpiControl AF: 0.200

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	Alpha-1-antitrypsin deficiency (3)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	PI M1-ALA213 (1)
-	-	1	PI, M1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	0.0090
DANN	Benign	0.31
DEOGEN2	Benign	0.12	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.0056	T
MetaRNN	Benign	0.000018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.63	N
PhyloP100		-0.18
PrimateAI	Benign	0.21	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.26
Sift	Benign	0.60	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.023
MPC		0.050
ClinPred		0.0091	T
GERP RS		-9.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.068
gMVP		0.23
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs6647; hg19: chr14-94847415; COSMIC: COSV63346575; COSMIC: COSV63346575;