Genetic Variant FAM216A:p.Arg154His (chr12-110486558-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_013300.3(FAM216A):c.461G>A(p.Arg154His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000319 in 1,613,740 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 2 hom. )

Consequence

FAM216A
NM_013300.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.634

Variant links:

Genes affected

FAM216A (HGNC:30180): (family with sequence similarity 216 member A)

FAM216A links:

LOC124903016 (HGNC:):

LOC124903016 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0044881105).

BP6

Variant 12-110486558-G-A is Benign according to our data. Variant chr12-110486558-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2356737.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM216A	NM_013300.3 link	c.461G>A	p.Arg154His	missense_variant	Exon 5 of 7	ENST00000377673.10	NP_037432.2	Q8WUB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM216A	ENST00000377673.10 link	c.461G>A	p.Arg154His	missense_variant	Exon 5 of 7	1	NM_013300.3	ENSP00000366901.5		Q8WUB2

Frequencies

GnomAD3 genomes

AF:

0.000349

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.0107

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000586

AC:

147

AN:

251052

Hom.:

AF XY:

0.000575

AC XY:

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.0110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000247

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000316

AC:

462

AN:

1461544

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

234

AN XY:

727044

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.0000448

Gnomad4 ASJ exome

AF:

0.0107

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000119

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000348

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.0107

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000611

Hom.:

Bravo

AF:

0.000374

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000404

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Jan 26, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.0067

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.74

M_CAP

Benign

0.0026

MetaRNN

Benign

0.0045

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.18

PrimateAI

Benign

0.20

PROVEAN

Benign

-0.90

REVEL

Benign

0.022

Sift

Benign

0.40

Sift4G

Benign

0.50

Polyphen

0.0090

Vest4

0.17

MVP

0.040

MPC

0.17

ClinPred

0.024

GERP RS

-0.93

Varity_R

0.017

gMVP

0.035

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over