Genetic Variant NM_138389.4:c.347T>C (chr4-38878425-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_138389.4(FAM114A1):c.347T>C(p.Leu116Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.265 in 1,575,556 control chromosomes in the GnomAD database, including 58,026 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.27 ( 6107 hom., cov: 32)

Exomes 𝑓: 0.26 ( 51919 hom. )

Consequence

FAM114A1
NM_138389.4 missense, splice_region

Scores

Splicing: ADA: 0.00001349

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.89

Publications

23 publications found

Variant links:

Genes affected

FAM114A1 (HGNC:25087): (family with sequence similarity 114 member A1) The protein encoded by this gene belongs to the FAM114 family and may play a role in neuronal cell development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2017]

FAM114A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.933842E-4).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM114A1	NM_138389.4 link	c.347T>C	p.Leu116Pro	missense_variant, splice_region_variant	Exon 3 of 15	ENST00000358869.5	NP_612398.2	Q8IWE2-1A1MMZ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
FAM114A1	ENST00000358869.5 link	c.347T>C	p.Leu116Pro	missense_variant, splice_region_variant	Exon 3 of 15	1	NM_138389.4	ENSP00000351740.2	Q8IWE2-1
FAM114A1	ENST00000510213.5 link	c.347T>C	p.Leu116Pro	missense_variant, splice_region_variant	Exon 2 of 3	2		ENSP00000422965.1	D6R9C9
FAM114A1	ENST00000515037.5 link	c.-274+10591T>C		intron_variant	Intron 1 of 12	2		ENSP00000424115.1	Q8IWE2-2

Frequencies

GnomAD3 genomes

AF:

0.274

AC:

41664

AN:

152010

Hom.:

6085

Cov.:

show subpopulations

Gnomad AFR

AF:

0.310

Gnomad AMI

AF:

0.212

Gnomad AMR

AF:

0.208

Gnomad ASJ

AF:

0.211

Gnomad EAS

AF:

0.0841

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.361

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.284

Gnomad OTH

AF:

0.229

GnomAD2 exomes

AF:

0.250

AC:

54669

AN:

218980

AF XY:

0.241

show subpopulations

Gnomad AFR exome

AF:

0.315

Gnomad AMR exome

AF:

0.271

Gnomad ASJ exome

AF:

0.221

Gnomad EAS exome

AF:

0.0865

Gnomad FIN exome

AF:

0.355

Gnomad NFE exome

AF:

0.269

Gnomad OTH exome

AF:

0.251

GnomAD4 exome

AF:

0.264

AC:

376155

AN:

1423428

Hom.:

51919

Cov.:

AF XY:

0.260

AC XY:

183311

AN XY:

703788

show subpopulations

African (AFR)

AF:

0.310

AC:

10115

AN:

32602

American (AMR)

AF:

0.261

AC:

10624

AN:

40684

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

5173

AN:

23338

East Asian (EAS)

AF:

0.0732

AC:

2883

AN:

39364

South Asian (SAS)

AF:

0.144

AC:

11531

AN:

79806

European-Finnish (FIN)

AF:

0.348

AC:

18041

AN:

51862

Middle Eastern (MID)

AF:

0.130

AC:

720

AN:

5558

European-Non Finnish (NFE)

AF:

0.277

AC:

302048

AN:

1091438

Other (OTH)

AF:

0.256

AC:

15020

AN:

58776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

13311

26622

39933

53244

66555

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10086

20172

30258

40344

50430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.274

AC:

41727

AN:

152128

Hom.:

6107

Cov.:

AF XY:

0.271

AC XY:

20137

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.311

AC:

12883

AN:

41472

American (AMR)

AF:

0.208

AC:

3183

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.211

AC:

733

AN:

3472

East Asian (EAS)

AF:

0.0847

AC:

439

AN:

5186

South Asian (SAS)

AF:

0.135

AC:

652

AN:

4824

European-Finnish (FIN)

AF:

0.361

AC:

3823

AN:

10576

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.284

AC:

19291

AN:

67990

Other (OTH)

AF:

0.234

AC:

493

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1533

3065

4598

6130

7663

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

422

844

1266

1688

2110

<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:

0.264

Hom.:

15017

Bravo

AF:

0.266

TwinsUK

AF:

0.270

AC:

1001

ALSPAC

AF:

0.267

AC:

1030

ESP6500AA

AF:

0.309

AC:

1355

ESP6500EA

AF:

0.268

AC:

2303

ExAC

AF:

0.243

AC:

29456

Asia WGS

AF:

0.158

AC:

551

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

0.0080

(source)

DANN

Benign

0.082

DEOGEN2

Benign

0.00018

.;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.0012

LIST_S2

Benign

0.11

T;T

MetaRNN

Benign

0.00089

T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.75

.;N

PhyloP100

-1.9

PrimateAI

Benign

0.25

PROVEAN

Benign

2.5

N;N

REVEL

Benign

0.044

Sift

Benign

0.94

T;T

Sift4G

Benign

0.32

T;T

Polyphen

0.0

.;B

Vest4

0.0080

MPC

0.10

ClinPred

0.0088

GERP RS

-9.5

Varity_R

0.020

gMVP

0.14

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000013

dbscSNV1_RF

Benign

0.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over