rs386834164

Variant names:

• chr14-102930400-C-T
• rs386834164
• NM_030943.4:c.1170-6C>T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030943.4(AMN):​c.1170-6C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00178 in 1,515,198 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0029 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0017 (11 hom.)
• Consequence: AMN NM_030943.4 splice_region, intron
• Scores: Splicing: ADA: 0.00006617
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:1
• Conservation: PhyloP100: -0.368

Genes affected

AMN (HGNC:14604): (amnion associated transmembrane protein) The protein encoded by this gene is a type I transmembrane protein. It is thought to modulate bone morphogenetic protein (BMP) receptor function by serving as an accessory or coreceptor, and thus facilitates or hinders BMP binding. It is known that the mouse AMN gene is expressed in the extraembryonic visceral endoderm layer during gastrulation, but it is found to be mutated in amnionless mouse. The encoded protein has sequence similarity to short gastrulation (Sog) and procollagen IIA proteins in Drosophila. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00287 (437/152236) while in subpopulation NFE AF= 0.00194 (132/67970). AF 95% confidence interval is 0.00167. There are 6 homozygotes in gnomad4. There are 284 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AMN	NM_030943.4	c.1170-6C>T		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000299155.10	NP_112205.2
AMN	NM_001425246.1	c.1008-6C>T		splice_region_variant, intron_variant	Intron 10 of 11		NP_001412175.1
AMN	XM_011537203.4	c.1008-6C>T		splice_region_variant, intron_variant	Intron 10 of 11		XP_011535505.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AMN	ENST00000299155.10	c.1170-6C>T		splice_region_variant, intron_variant	Intron 10 of 11	1	NM_030943.4	ENSP00000299155.6

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152128 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0253

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00194

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00212 AC: 241 AN: 113898 Hom.: 1 AF XY: 0.00200 AC XY: 126 AN XY: 62898

Gnomad AFR exome AF: 0.000285

Gnomad AMR exome AF: 0.000613

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000443

Gnomad FIN exome AF: 0.0254

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00140

GnomAD4 exome AF: 0.00165 AC: 2254 AN: 1362962 Hom.: 11 Cov.: 36 AF XY: 0.00159 AC XY: 1070 AN XY: 671594

Gnomad4 AFR exome AF: 0.000275

Gnomad4 AMR exome AF: 0.000645

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000597

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.00136

Gnomad4 OTH exome AF: 0.00148

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152236 Hom.: 6 Cov.: 34 AF XY: 0.00382 AC XY: 284 AN XY: 74424

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0253

Gnomad4 NFE AF: 0.00194

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00194 Hom.: 1

Bravo AF: 0.00102

Asia WGS AF: 0.000579 AC: 2 AN: 3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Imerslund-Grasbeck syndrome Pathogenic:1 Benign:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juha Muilu Group; Institute for Molecular Medicine Finland (FIMM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified Uncertain:1

Nov 01, 2016

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	5.7
DANN	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000066
dbscSNV1_RF	Benign	0.0
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: rs386834164; hg19: chr14-103396737;