rs187818578

Variant names:

• chr4-76268715-C-T
• rs187818578
• NM_001136570.3:c.616C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001136570.3(FAM47E):​c.616C>T​(p.His206Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000505 in 1,551,496 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (1 hom.)
• Consequence: FAM47E NM_001136570.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0440
• Publications: 3 publications found

Genes affected

FAM47E (HGNC:34343): (family with sequence similarity 47 member E) Enables enzyme activator activity. Involved in positive regulation of histone methylation and protein localization to chromatin. Located in chromatin; cytoplasm; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

FAM47E-STBD1 (HGNC:44667): (FAM47E-STBD1 readthrough) This locus represents naturally occurring read-through transcription between the neighboring FAM47E (family with sequence similarity 47, member E) and STBD1 (starch binding domain 1) genes on chromosome 4. The read-through transcript encodes a protein that shares sequence identity with the upstream gene product but its C-terminal region is distinct due to frameshifts relative to the downstream gene. [provided by RefSeq, Jul 2011]

ENSG00000287401 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.04735887).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM47E	NM_001136570.3	c.616C>T	p.His206Tyr	missense_variant	Exon 4 of 8	ENST00000424749.7	NP_001130042.1
FAM47E-STBD1	NM_001242939.2	c.616C>T	p.His206Tyr	missense_variant	Exon 4 of 7		NP_001229868.1
FAM47E	NM_001242936.1	c.277C>T	p.His93Tyr	missense_variant	Exon 4 of 8		NP_001229865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM47E	ENST00000424749.7	c.616C>T	p.His206Tyr	missense_variant	Exon 4 of 8	5	NM_001136570.3	ENSP00000409423.2
FAM47E-STBD1	ENST00000515604.5	c.616C>T	p.His206Tyr	missense_variant	Exon 4 of 7	2		ENSP00000422067.1

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000256 AC: 40 AN: 156396 AF XY: 0.000193

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.0000406

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.000612

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000529 AC: 740 AN: 1399194 Hom.: 1 Cov.: 30 AF XY: 0.000478 AC XY: 330 AN XY: 690102

African (AFR) AF: 0.0000317 AC: 1 AN: 31580

American (AMR) AF: 0.0000561 AC: 2 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.00 AC: 0 AN: 35706

South Asian (SAS) AF: 0.00 AC: 0 AN: 79212

European-Finnish (FIN) AF: 0.0000609 AC: 3 AN: 49270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.000671 AC: 724 AN: 1078890

Other (OTH) AF: 0.000172 AC: 10 AN: 57996

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152302 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41556

American (AMR) AF: 0.000196 AC: 3 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000573 AC: 39 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000610 Hom.: 0

Bravo AF: 0.000329

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000943 AC: 3

ExAC AF: 0.000162 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.616C>T (p.H206Y) alteration is located in exon 4 (coding exon 4) of the FAM47E gene. This alteration results from a C to T substitution at nucleotide position 616, causing the histidine (H) at amino acid position 206 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.2
DANN	Benign	0.90
DEOGEN2	Benign	0.015	.;.;.;.;T;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.71	T;T;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.047	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	.;.;.;.;N;.;.
PhyloP100		-0.044
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N;N;.;.;N;N;.
REVEL	Benign	0.035
Sift	Benign	0.081	T;T;.;.;T;T;.
Sift4G	Benign	0.82	T;T;.;.;T;T;T
Polyphen		0.50	P;P;.;.;B;.;.
Vest4		0.18
MVP		0.014
MPC		0.069
ClinPred		0.027	T
GERP RS		-2.9
Varity_R		0.051
gMVP		0.074
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs187818578; hg19: chr4-77189868; COSMIC: COSV99046053;