4-38878425-T-C

Variant names:

• chr4-38878425-T-C
• rs11555334
• NM_138389.4:c.347T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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

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]

ACMG classification

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	c.347T>C	p.Leu116Pro	missense_variant, splice_region_variant	Exon 3 of 15	ENST00000358869.5	NP_612398.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41664 AN: 152010 Hom.: 6085 Cov.: 32

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

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.: 32 AF XY: 0.260 AC XY: 183311 AN XY: 703788

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

GnomAD4 genome AF: 0.274 AC: 41727 AN: 152128 Hom.: 6107 Cov.: 32 AF XY: 0.271 AC XY: 20137 AN XY: 74344

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: 37 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19291 AN: 67990

Other (OTH) AF: 0.234 AC: 493 AN: 2110

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	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.0080
DANN	Benign	0.082
DEOGEN2	Benign	0.00018	.;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.11	T;T
MetaRNN	Benign	0.00089	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.75	.;N
PhyloP100		-1.9
PrimateAI	Benign	0.25	T
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	T
GERP RS		-9.5
Varity_R		0.020
gMVP		0.14
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs11555334; hg19: chr4-38880046; COSMIC: COSV62672948;