Genetic Variant FAM220A:p.Arg127Pro (chr7-6330775-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001037163.2(FAM220A):c.380G>C(p.Arg127Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 151,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

FAM220A
NM_001037163.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.597

Publications

28 publications found

Variant links:

Genes affected

FAM220A (HGNC:22422): (family with sequence similarity 220 member A) Predicted to enable STAT family protein binding activity. Predicted to be involved in negative regulation of transcription by RNA polymerase II and protein dephosphorylation. Predicted to act upstream of or within positive regulation of protein binding activity. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FAM220A links:

SMIM10L3 (HGNC:56768):

SMIM10L3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21647727).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM220A	NM_001037163.2 link	c.380G>C	p.Arg127Pro	missense_variant	Exon 2 of 2	ENST00000313324.9	NP_001032240.1
SMIM10L3	NM_001395995.1 link	c.*440G>C		3_prime_UTR_variant	Exon 2 of 2	ENST00000578372.2	NP_001382924.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM220A	ENST00000313324.9 link	c.380G>C	p.Arg127Pro	missense_variant	Exon 2 of 2	1	NM_001037163.2	ENSP00000317289.4	Q7Z4H9
SMIM10L3	ENST00000578372.2 link	c.*440G>C		3_prime_UTR_variant	Exon 2 of 2	1	NM_001395995.1	ENSP00000464009.1	A0A0C4DGP1
FAM220A	ENST00000524898.2 link	c.380G>C	p.Arg127Pro	missense_variant	Exon 2 of 2	3		ENSP00000432444.2	E9PQY0
FAM220A	ENST00000530143.2 link	c.380G>C	p.Arg127Pro	missense_variant	Exon 2 of 2	4		ENSP00000436886.2	E9PQC6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151924

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151924

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74170

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41386

American (AMR)

AF:

0.00

AC:

AN:

15228

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

16724

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

9.7

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.00018

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.097

LIST_S2

Benign

0.26

.;T

M_CAP

Benign

0.0048

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

0.60

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.58

N;.

REVEL

Benign

0.16

Sift

Benign

0.28

T;.

Sift4G

Benign

0.26

T;T

Polyphen

0.99

D;D

Vest4

0.36

MutPred

0.18

Loss of MoRF binding (P = 0.0034);Loss of MoRF binding (P = 0.0034);

MVP

0.13

MPC

0.038

ClinPred

0.22

GERP RS

4.2

Varity_R

0.17

gMVP

0.21

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over