15-74902687-T-G

Variant names:

• chr15-74902687-T-G
• rs780874223
• NM_020447.5:c.529A>C

Variant summary

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

The NM_020447.5(FAM219B):​c.529A>C​(p.Met177Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M177V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: FAM219B NM_020447.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870
• Publications: 0 publications found

Genes affected

FAM219B (HGNC:24695): (family with sequence similarity 219 member B)

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=0.04452586).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020447.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM219B	NM_020447.5	MANE Select	c.529A>C	p.Met177Leu	missense	Exon 5 of 5	NP_065180.1	Q5XKK7-1
	FAM219B	NM_001321920.2		c.529A>C	p.Met177Leu	missense	Exon 5 of 6	NP_001308849.1	Q5XKK7-1
	FAM219B	NM_001321921.2		c.529A>C	p.Met177Leu	missense	Exon 5 of 6	NP_001308850.1	Q5XKK7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FAM219B	ENST00000357635.10	TSL:1 MANE Select	c.529A>C	p.Met177Leu	missense	Exon 5 of 5	ENSP00000350260.5	Q5XKK7-1
	FAM219B	ENST00000563119.5	TSL:1	c.529A>C	p.Met177Leu	missense	Exon 5 of 6	ENSP00000454719.1	Q5XKK7-1
	FAM219B	ENST00000565772.5	TSL:1	c.271A>C	p.Met91Leu	missense	Exon 4 of 4	ENSP00000455248.1	H3BPC2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460922 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726710

African (AFR) AF: 0.0000299 AC: 1 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 85926

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111560

Other (OTH) AF: 0.00 AC: 0 AN: 60366

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.8
DANN	Benign	0.72
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.087
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.026
Sift	Benign	0.17	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.15
MutPred		0.19		Gain of relative solvent accessibility (P = 0.0166)
MVP		0.014
MPC		0.26
ClinPred		0.063	T
GERP RS		0.23
Varity_R		0.047
gMVP		0.052

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: rs780874223; hg19: chr15-75195028;