chr4-76271637-C-A

Variant names:

• chr4-76271637-C-A
• rs375151279
• NM_001136570.3:c.739C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001136570.3(FAM47E):​c.739C>A​(p.His247Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,399,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: FAM47E NM_001136570.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.81
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.015230566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM47E	NM_001136570.3	c.739C>A	p.His247Asn	missense_variant	Exon 5 of 8	ENST00000424749.7	NP_001130042.1
FAM47E-STBD1	NM_001242939.2	c.739C>A	p.His247Asn	missense_variant	Exon 5 of 7		NP_001229868.1
FAM47E	NM_001242936.1	c.445C>A	p.His149Asn	missense_variant	Exon 5 of 8		NP_001229865.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM47E	ENST00000424749.7	c.739C>A	p.His247Asn	missense_variant	Exon 5 of 8	5	NM_001136570.3	ENSP00000409423.2
FAM47E-STBD1	ENST00000515604.5	c.739C>A	p.His247Asn	missense_variant	Exon 5 of 7	2		ENSP00000422067.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000252 AC: 4 AN: 158608 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000808

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000162

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000143 AC: 20 AN: 1399900 Hom.: 0 Cov.: 32 AF XY: 0.0000145 AC XY: 10 AN XY: 690422

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.0000840 AC: 3 AN: 35710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49488

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000130 AC: 14 AN: 1079080

Other (OTH) AF: 0.0000344 AC: 2 AN: 58172

GnomAD4 genome Cov.: 33

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000390 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.739C>A (p.H247N) alteration is located in exon 5 (coding exon 5) of the FAM47E gene. This alteration results from a C to A substitution at nucleotide position 739, causing the histidine (H) at amino acid position 247 to be replaced by an asparagine (N). 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	0.10
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.057
DANN	Benign	0.58
DEOGEN2	Benign	0.053	.;.;T;.;.
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.37	T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	.;.;L;.;.
PhyloP100		-1.8
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.6	D;.;D;D;.
REVEL	Benign	0.022
Sift	Benign	0.21	T;.;T;T;.
Sift4G	Benign	0.12	T;.;T;T;D
Polyphen		0.013	B;.;B;.;.
Vest4		0.15
MutPred		0.45		.;.;Gain of glycosylation at S246 (P = 0.1934);Gain of glycosylation at S246 (P = 0.1934);.;
MVP		0.014
MPC		0.033
ClinPred		0.053	T
GERP RS		-9.5
Varity_R		0.068
gMVP		0.087
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: rs375151279; hg19: chr4-77192790;