chr6-4068802-C-T

Variant names:

• chr6-4068802-C-T
• rs754475677
• NM_173563.3:c.1421G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_173563.3(FAM217A):​c.1421G>A​(p.Arg474Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: FAM217A NM_173563.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.115

Genes affected

FAM217A (HGNC:21362): (family with sequence similarity 217 member A)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044210345).
• BP6: Variant 6-4068802-C-T is Benign according to our data. Variant chr6-4068802-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2309752.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM217A	NM_173563.3	c.1421G>A	p.Arg474Gln	missense_variant	Exon 7 of 7	ENST00000274673.8	NP_775834.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM217A	ENST00000274673.8	c.1421G>A	p.Arg474Gln	missense_variant	Exon 7 of 7	1	NM_173563.3	ENSP00000274673.3
FAM217A	ENST00000639338.1	c.1823G>A	p.Arg608Gln	missense_variant	Exon 9 of 9	5		ENSP00000492773.1
FAM217A	ENST00000380188.2	n.1830G>A		non_coding_transcript_exon_variant	Exon 5 of 5	2
FAM217A	ENST00000469157.5	n.391+4473G>A		intron_variant	Intron 2 of 2	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251330 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135836

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461814 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727204

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 30, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0056	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.060	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.63	N;.
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.041
Sift	Benign	0.27	T;.
Sift4G	Benign	0.19	T;.
Polyphen		0.17	B;.
Vest4		0.080
MutPred		0.32		Loss of MoRF binding (P = 0.0186);.;
MVP		0.16
MPC		0.040
ClinPred		0.057	T
GERP RS		0.16
Varity_R		0.049
gMVP		0.046

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

Publications

LitVar

Other links and lift over

dbSNP: rs754475677; hg19: chr6-4069036; COSMIC: COSV51158954; COSMIC: COSV51158954;