22-18528559-C-G

Variant names:

• chr22-18528559-C-G
• rs748405988
• NM_001242313.1:c.297C>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001242313.1(TMEM191B):​c.297C>G​(p.Ser99Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 15)
  • Exomes 𝑓: 0.00089 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TMEM191B NM_001242313.1 missense, splice_region
• Scores: Splicing: ADA: 0.0005916
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.172

Genes affected

TMEM191B (HGNC:33600): (transmembrane protein 191B) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039980263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMEM191B	NM_001242313.1	c.297C>G	p.Ser99Arg	missense_variant, splice_region_variant	Exon 2 of 9	ENST00000612978.5	NP_001229242.1
TMEM191B	XM_011546160.4	c.297C>G	p.Ser99Arg	missense_variant, splice_region_variant	Exon 2 of 10		XP_011544462.1
TMEM191B	XR_951236.3	n.476C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMEM191B	ENST00000612978.5	c.297C>G	p.Ser99Arg	missense_variant, splice_region_variant	Exon 2 of 9	5	NM_001242313.1	ENSP00000481358.1
TMEM191B	ENST00000613577.5	c.297C>G	p.Ser99Arg	missense_variant, splice_region_variant	Exon 2 of 10	3		ENSP00000483146.2
TMEM191B	ENST00000614395.4	n.476C>G		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes AF: 0.000939 AC: 106 AN: 112938 Hom.: 0 Cov.: 15

Gnomad AFR AF: 0.000454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000412

Gnomad ASJ AF: 0.00100

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00145

Gnomad OTH AF: 0.00277

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000886 AC: 1153 AN: 1301004 Hom.: 0 Cov.: 25 AF XY: 0.000898 AC XY: 575 AN XY: 640458

Gnomad4 AFR exome AF: 0.000305

Gnomad4 AMR exome AF: 0.000319

Gnomad4 ASJ exome AF: 0.000426

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000456

Gnomad4 FIN exome AF: 0.000340

Gnomad4 NFE exome AF: 0.000996

Gnomad4 OTH exome AF: 0.00108

GnomAD4 genome AF: 0.000938 AC: 106 AN: 113028 Hom.: 0 Cov.: 15 AF XY: 0.000932 AC XY: 50 AN XY: 53654

Gnomad4 AFR AF: 0.000453

Gnomad4 AMR AF: 0.000412

Gnomad4 ASJ AF: 0.00100

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000368

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00145

Gnomad4 OTH AF: 0.00273

Alfa AF: 0.00116 Hom.: 1

ExAC AF: 0.000263 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 02, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.297C>G (p.S99R) alteration is located in exon 2 (coding exon 2) of the TMEM191B gene. This alteration results from a C to G substitution at nucleotide position 297, causing the serine (S) at amino acid position 99 to be replaced by an arginine (R). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	17
DANN	Benign	0.70
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.47	T
MetaRNN	Benign	0.040	T
PrimateAI	Pathogenic	0.85	D
Sift4G	Benign	0.36	T
Vest4		0.12
MVP		0.24
GERP RS		1.5
Varity_R		0.068
gMVP		0.047

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00059
dbscSNV1_RF	Benign	0.098
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: rs748405988; hg19: chr22-20378426;