rs35318502

Variant names:

• chr19-41354198-G-A
• rs35318502
• ENST00000539627.5:c.-30+2996G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The ENST00000539627.5(TMEM91):​c.-30+2996G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00098 in 430,676 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: TMEM91 ENST00000539627.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.143
• Publications: 4 publications found

Genes affected

TMEM91 (HGNC:32393): (transmembrane protein 91) Predicted to act upstream of or within hematopoietic progenitor cell differentiation. Predicted to be integral component of membrane. Predicted to be active in intracellular membrane-bounded organelle and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000255730 (HGNC:):

B9D2 (HGNC:28636): (B9 domain containing 2) This gene encodes a B9 domain protein, which are exclusively found in ciliated organisms. The gene is upregulated during mucociliary differentiation, and the encoded protein localizes to basal bodies and cilia. Disrupting expression of this gene results in ciliogenesis defects. [provided by RefSeq, Oct 2009]

TGFB1 (HGNC:11766): (transforming growth factor beta 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGFB family members. This encoded protein regulates cell proliferation, differentiation and growth, and can modulate expression and activation of other growth factors including interferon gamma and tumor necrosis factor alpha. This gene is frequently upregulated in tumor cells, and mutations in this gene result in Camurati-Engelmann disease. [provided by RefSeq, Aug 2016]

TGFB1 Gene-Disease associations (from GenCC):

• Camurati-Engelmann disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, Ambry Genetics, PanelApp Australia
• inflammatory bowel disease, immunodeficiency, and encephalopathy

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• cystic fibrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041075945).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000539627.5. 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
	B9D2	NM_030578.4	MANE Select	c.*502C>T		downstream_gene	N/A	NP_085055.2	Q9BPU9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMEM91	ENST00000539627.5	TSL:1	c.-30+2996G>A		intron	N/A	ENSP00000441900.1	F5GWC9
	TMEM91	ENST00000889862.1		c.-147G>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 4	ENSP00000559921.1
	TMEM91	ENST00000604123.5	TSL:3	c.25G>A	p.Val9Met	missense	Exon 1 of 4	ENSP00000474871.1	S4R3Y8

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00755

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00110 AC: 16 AN: 14570 AF XY: 0.00101

Gnomad AFR exome AF: 0.00796

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00216

GnomAD4 exome AF: 0.000302 AC: 84 AN: 278346 Hom.: 1 Cov.: 0 AF XY: 0.000302 AC XY: 43 AN XY: 142346

African (AFR) AF: 0.00723 AC: 60 AN: 8296

American (AMR) AF: 0.000559 AC: 6 AN: 10738

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9712

East Asian (EAS) AF: 0.00 AC: 0 AN: 25050

South Asian (SAS) AF: 0.000111 AC: 1 AN: 9026

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1362

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 174804

Other (OTH) AF: 0.000962 AC: 17 AN: 17678

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74486

African (AFR) AF: 0.00753 AC: 313 AN: 41592

American (AMR) AF: 0.00124 AC: 19 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00160 Hom.: 0

Bravo AF: 0.00280

ExAC AF: 0.0000961 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.5
DANN	Benign	0.96
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.46	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.0041	T
PhyloP100		-0.14
Vest4		0.15
MVP		0.19
GERP RS		1.1
PromoterAI		0.013	Neutral
Mutation Taster		=99/1	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35318502; hg19: chr19-41860103;