9-35819970-T-C

Variant names:

• chr9-35819970-T-C
• rs1005408695
• NM_001012446.4:c.773A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001012446.4(FAM221B):​c.773A>G​(p.Tyr258Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,728 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (1 hom.)
• Consequence: FAM221B NM_001012446.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.16

Genes affected

FAM221B (HGNC:30762): (family with sequence similarity 221 member B)

ENSG00000285645 (HGNC:):

TMEM8B (HGNC:21427): (transmembrane protein 8B) Involved in cell-matrix adhesion. Located in cell surface and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30835617).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FAM221B	NM_001012446.4	c.773A>G	p.Tyr258Cys	missense_variant	Exon 4 of 7	ENST00000423537.7	NP_001012448.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM221B	ENST00000423537.7	c.773A>G	p.Tyr258Cys	missense_variant	Exon 4 of 7	1	NM_001012446.4	ENSP00000415299.2
ENSG00000285645	ENST00000650284.1	n.-37A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 3 of 10			ENSP00000498023.1
ENSG00000285645	ENST00000650284.1	n.-37A>G		non_coding_transcript_exon_variant	Exon 3 of 10			ENSP00000498023.1
ENSG00000285645	ENST00000650284.1	n.-37A>G		5_prime_UTR_variant	Exon 3 of 10			ENSP00000498023.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461728 Hom.: 1 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727166

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.773A>G (p.Y258C) alteration is located in exon 4 (coding exon 3) of the FAM221B gene. This alteration results from a A to G substitution at nucleotide position 773, causing the tyrosine (Y) at amino acid position 258 to be replaced by a cysteine (C). 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	Pathogenic	0.69
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.022	T;.
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D;D
REVEL	Benign	0.17
Sift	Benign	0.12	T;D
Sift4G	Uncertain	0.022	D;.
Polyphen		1.0	D;.
Vest4		0.85
MutPred		0.42		Gain of catalytic residue at Y258 (P = 0.0523);Gain of catalytic residue at Y258 (P = 0.0523);
MVP		0.31
MPC		0.43
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.18
gMVP		0.58

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: rs1005408695; hg19: chr9-35819967;