rs12720061

chr2-219575104-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002191.4(INHA):c.679G>A(p.Gly227Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00523 in 1,614,050 control chromosomes in the GnomAD database, including 370 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.027 (191 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (179 hom.)
• Consequence: INHA NM_002191.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.63

Genes affected

INHA (HGNC:6065): (inhibin subunit alpha) This gene encodes a member of the TGF-beta (transforming growth factor-beta) superfamily of proteins. The encoded preproprotein is proteolytically processed to generate multiple peptide products, including the alpha subunit of the inhibin A and B protein complexes. These complexes negatively regulate follicle stimulating hormone secretion from the pituitary gland. Inhibins have also been implicated in regulating numerous cellular processes including cell proliferation, apoptosis, immune response and hormone secretion. Mutations in this gene may be associated with male infertility and premature ovarian failure in female human patients. [provided by RefSeq, Aug 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015151501).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0902 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
INHA	NM_002191.4	c.679G>A	p.Gly227Arg	missense_variant	2/2	ENST00000243786.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
INHA	ENST00000243786.3	c.679G>A	p.Gly227Arg	missense_variant	2/2	1	NM_002191.4	P1

Frequencies

GnomAD3 genomes AF: 0.0268 AC: 4081 AN: 152210 Hom.: 191 Cov.: 33

Gnomad AFR AF: 0.0926

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00749 AC: 1880 AN: 251010 Hom.: 76 AF XY: 0.00579 AC XY: 786 AN XY: 135738

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.00526

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000247

Gnomad OTH exome AF: 0.00424

GnomAD4 exome AF: 0.00298 AC: 4351 AN: 1461722 Hom.: 179 Cov.: 32 AF XY: 0.00262 AC XY: 1907 AN XY: 727166

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.00601

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000195

Gnomad4 OTH exome AF: 0.00657

GnomAD4 genome AF: 0.0269 AC: 4092 AN: 152328 Hom.: 191 Cov.: 33 AF XY: 0.0260 AC XY: 1940 AN XY: 74500

Gnomad4 AFR AF: 0.0926

Gnomad4 AMR AF: 0.0116

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00462 Hom.: 54

Bravo AF: 0.0314

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0908 AC: 400

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00895 AC: 1087

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.19	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.26	T
Polyphen		0.062	B
Vest4		0.22
MutPred		0.12		Gain of methylation at G227 (P = 0.0138);
MVP		0.89
MPC		0.25
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.068
gMVP		0.55

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: rs12720061; hg19: chr2-220439826;